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  • 1. Bonaïti, Bernard
    et al.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bonaïti-Pellié, Catherine
    Planté-Bordeneuve, Violaine
    TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

  • 2. Cheng, Timothy H T
    et al.
    Gorman, Maggie
    Martin, Lynn
    Barclay, Ella
    Casey, Graham
    Saunders, Brian
    Thomas, Huw
    Clark, Sue
    Tomlinson, Ian
    Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 2Article in journal (Refereed)
    Abstract [en]

    The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

  • 3. Corcia, Philippe
    et al.
    Ingre, Caroline
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Blasco, Helene
    Press, Rayomand
    Praline, Julien
    Antar, Catherine
    Veyrat-Durebex, Charlotte
    Guettard, Yves-Olivier
    Camu, William
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vourc'h, Patrick
    Andres, Christian R
    Homozygous SMN2 deletion is a protective factor in the Swedish ALS population2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 5, p. 588-591Article in journal (Refereed)
    Abstract [en]

    Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations. European Journal of Human Genetics (2012) 20, 588-591; doi:10.1038/ejhg.2011.255; published online 25 January 2012

  • 4.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, p. 81-84Article in journal (Refereed)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 5. Farias, Fabiana H. G.
    et al.
    Dahlqvist, Johanna
    Kozyrev, Sergey V.
    Leonard, Dag
    Wilbe, Maria
    Abramov, Sergei N.
    Alexsson, Andrei
    Pielberg, Gerli R.
    Hansson-Hamlin, Helene
    Andersson, Goran
    Tandre, Karolina
    Bengtsson, Anders A.
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Syvanen, Ann-Christine
    Sandling, Johanna K.
    Eloranta, Maija-Leena
    Rönnblom, Lars
    Lindblad-Toh, Kerstin
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 432-441Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted resequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0 .014 , CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-Ul-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

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  • 6. Franke, Lude
    et al.
    el Bannoudi, Hanane
    Jansen, Diahann T. S. L.
    Kok, Klaas
    Trynka, Gosia
    Diogo, Dorothee
    Swertz, Morris
    Fransen, Karin
    Knevel, Rachel
    Gutierrez-Achury, Javier
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Greenberg, Jeffrey D.
    Kremer, Joel
    Pappas, Dimitrios A.
    Kanterakis, Alexandros
    Weersma, Rinse K.
    van der Helm-van Mil, Annette H. M.
    Guryev, Viktor
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Gregersen, Peter K.
    Plenge, Robert M.
    Wijmenga, Cisca
    Huizinga, Tom W-J
    Ioan-Facsinay, Andreea
    Toes, Rene E. M.
    Zhernakova, Alexandra
    Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 2, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fc gamma receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P = 0.002, OR = 1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P = 0.023, OR = 1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.

  • 7. Gogol, I.
    et al.
    Osmanovic, A.
    Martens, H.
    Widjaja, M.
    Mueller, K.
    Schreiber-Katz, O.
    Schmidt, G.
    Auber, B.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Ludolph, A.
    Weishaupt, J.
    Brand, F.
    Petri, S.
    Weber, R. G.
    Rare heterozygous DHTKD1 variants in patients with amyotrophic lateral sclerosis2020In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 28, p. 428-429Article in journal (Other academic)
  • 8. Grisoni, Marie-Lise
    et al.
    Proust, Carole
    Alanne, Mervi
    DeSuremain, Maylis
    Salomaa, Veikko
    Kuulasmaa, Kari
    Cambien, François
    Nicaud, Viviane
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Virtamo, Jarmo
    Shields, Denis
    Kee, Frank
    Tiret, Laurence
    Evans, Alun
    Tregouet, David-Alexandre
    Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: the MORGAM Project.2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 12, p. 1512-20Article in journal (Refereed)
    Abstract [en]

    Interleukin-18 (IL-18) is a key inflammatory molecule suspected of being involved in the etiology of cardiovascular diseases (CVD). Five single nucleotide polymorphisms (SNPs) capturing the common genetic variation of the IL-18 gene (tag SNPs) were genotyped in five European prospective CVD cohorts including 1933 cases and 1938 non-cases as part of the MORGAM Project. Not a single SNP was found associated with CVD. However, a significant (P=0.002) gene-smoking interaction was observed. In smokers, the -105T allele was more frequent in cases than in non-cases (0.29 vs 0.25) and associated with an increased risk of disease (odds ratio (OR)=1.25 (1.07-1.45), P=0.005), whereas the inverse relationship tended to be observed in non-smokers (OR=0.90 (0.78-1.02), P=0.131). The gene-smoking interaction was broadly homogenous across the cohorts and was also observed through haplotype analyses. In conclusion, using the concerted effort of several European prospective CVD cohorts, we are able to show that one IL-18 tag SNP interacts with smoking to modulate the risk of developing CVD.

  • 9. Haworth, Simon
    et al.
    Kho, Pik Fang
    Lif Holgerson, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hwang, Liang-Dar
    Timpson, Nicholas J.
    Renteria, Miguel E.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Cuellar-Partida, Gabriel
    Assessment and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis2021In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 29, p. 300-308Article in journal (Refereed)
    Abstract [en]

    Hypothesis-free Mendelian randomization studies provide a way to assess the causal relevance of a trait across the human phenome but can be limited by statistical power, sample overlap or complicated by horizontal pleiotropy. The recently described latent causal variable (LCV) approach provides an alternative method for causal inference which might be useful in hypothesis-free experiments across human phenome. We developed an automated pipeline for phenome-wide tests using the LCV approach including steps to estimate partial genetic causality, filter to a meaningful set of estimates, apply correction for multiple testing and then present the findings in a graphical summary termed causal architecture plot. We apply this pipeline to body mass index (BMI) and lipid traits as exemplars of traits where there is strong prior expectation for causal effects, and to dental caries and periodontitis as exemplars of traits where there is a need for causal inference. The results for lipids and BMI suggest that these traits are best viewed as contributing factors on a multitude of traits and conditions, thus providing additional evidence that supports viewing these traits as targets for interventions to improve health. On the other hand, caries and periodontitis are best viewed as a downstream consequence of other traits and diseases rather than a cause of ill health. The automated pipeline is implemented in the Complex-Traits Genetics Virtual Lab (https:// vl.genoma.io) and results are available in. We propose causal architecture plots based on phenome-wide partial genetic causality estimates as a new way visualizing the overall causal map of the human phenome.

  • 10.
    Hawranek, Carolina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Maxon, J.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Andreas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Numan, Barbro
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cancer worry and willingness to undergo colonoscopy at different risk levels: results from a population-based survey in Sweden2020In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 28, p. 786-786Article in journal (Other academic)
  • 11. Iqbal, Zafar
    et al.
    Pihlstrom, Lasse
    Rengmark, Aina
    Henriksen, Sandra Pilar
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Toft, Mathias
    Rare variants in dementia genes and Parkinson's disease2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 12, p. 1661-1662Article in journal (Refereed)
  • 12.
    Jonasson, Jenni
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Juvonen, Vesa
    Sistonen, Pertti
    Ignatius, Jaakko
    Johansson, Daniel
    Björk, Erik
    Wahlström, Jan
    Melberg, Atle
    Holmgren, Gösta
    Forsgren, Lars
    Holmberg, Monica
    Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia2000In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 8, no 12, p. 918-922Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCAI gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.

  • 13.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Marie S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, p. 1266-1271Article in journal (Refereed)
    Abstract [en]

    This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

  • 14.
    Kaati, Gunnar
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Bygren, Lars Olov
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Edvinsson, Sören
    Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS).
    Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period2002In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 10, no 11, p. 682-688Article in journal (Refereed)
    Abstract [en]

    Overfeeding and overeating in families are traditions that are often transferred from generation to generation. Irrespective of these family traditions, food availability might lead to overfeeding, in its turn leading to metabolic adaptations. Apart from selection, could these adaptations to the social environment have transgenerational effects? This study will attempt to answer the following question: Can overeating during a child's slow growth period (SGP), before their prepubertal peak in growth velocity influence descendants' risk of death from cardiovascular disease and diabetes? Data were collected by following three cohorts born in 1890, 1905 and 1920 in Överkalix parish in northern Sweden up until death or 1995. The parents' or grandparents' access to food during their SGP was determined by referring to historical data on harvests and food prices, records of local community meetings and general historical facts. If food was not readily available during the father's slow growth period, then cardiovascular disease mortality of the proband was low. Diabetes mortality increased if the paternal grandfather was exposed to a surfeit of food during his slow growth period. (Odds Ratio 4.1, 95% confidence interval 1.33-12.93, P=0.01). Selection bias seemed to be unlikely. A nutrition-linked mechanism through the male line seems to have influenced the risk for cardiovascular and diabetes mellitus mortality.

  • 15.
    Kaati, Gunnar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bygren, Lars Olov
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Pembrey, Marcus
    Sjöstrom, Michael
    Transgenerational response to nutrition, early life circumstances and longevity2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 7, p. 784-790Article in journal (Refereed)
    Abstract [en]

    Nutrition might induce, at some loci, epigenetic or other changes that could be transmitted to the next generation impacting on health. The slow growth period (SGP) before the prepubertal peak in growth velocity has emerged as a sensitive period where different food availability is followed by different transgenerational response (TGR). The aim of this study is to investigate to what extent the probands own childhood circumstances are in fact the determinants of the findings. In the analysis, data from three random samples, comprising 271 probands and their 1626 parents and grandparents, left after exclusions because of missing data, were utilized. The availability of food during any given year was classified based on regional statistics. The ancestors' SGP was set at the ages of 8-12 years and the availability of food during these years classified as good, intermediate or poor. The probands' childhood circumstances were defined by the father's ownership of land, the number of siblings and order in the sibship, the death of parents and the parents' level of literacy. An earlier finding of a sex-specific influence from the ancestors' nutrition during the SGP, going from the paternal grandmother to the female proband and from the paternal grandfather to the male proband, was confirmed. In addition, a response from father to son emerged when childhood social circumstances of the son were accounted for. Early social circumstances influenced longevity for the male proband. TGRs to ancestors' nutrition prevailed as the main influence on longevity.

  • 16. Klar, Joakim
    et al.
    Raykova, Doroteya
    Gustafson, Elisabet
    Tothova, Iveta
    Ameur, Adam
    Wanders, Alkwin
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Biomedical Centre, Uppsala University, Uppsala, Sweden.
    Dahl, Niklas
    Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 12, p. 1679-1683Article in journal (Refereed)
    Abstract [en]

    Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin gamma-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.

  • 17.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bowne, Sara J
    The University of Texas Health Science Center, Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center .
    Daiger, Stephen P
    The University of Texas Health Science Center, Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center .
    Burstedt, Marie SI
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance2009In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 5, p. 651-655Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.

  • 18.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bowne, Sara J
    Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
    S Sullivan, Lori
    Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
    Daiger, Stephen P
    Laboratory for Molecular Diagnosis of Inherited Eye Diseases, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
    Burstedt, Marie S I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.2009In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 5, p. 651-655Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.

  • 19.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Kadzhaev, Konstantin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Burstedt, Marie SI
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 6, p. 664-671Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant cone dystrophy (CORD5) (MIM 600977) is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3) (MIM 608921) in two Swedish families. PITPNM3, known as a human homologue of the Drosophila retinal degeneration B (rdgB), lacks the N-terminal PIT domain needed for transport of phospholipids, renewal of photoreceptors membrane and providing the electroretinogram (ERG) response to light. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Our finding on the first mutation in the human homologue of Drosophila rdgB indicates novel pathways and a potential important role of the PITPNM3 in mammalian phototransduction.

  • 20. Laitman, Yael
    et al.
    Feng, Bing-Jian
    Zamir, Itay M
    The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
    Weitzel, Jeffrey N
    Duncan, Paul
    Port, Danielle
    Thirthagiri, Eswary
    Teo, Soo-Hwang
    Evans, Gareth
    Latif, Ayse
    Newman, William G
    Gershoni-Baruch, Ruth
    Zidan, Jamal
    Shimon-Paluch, Shani
    Goldgar, David
    Friedman, Eitan
    Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 2, p. 212-216Article in journal (Refereed)
    Abstract [en]

    The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.

  • 21. Lappalainen, Tuuli
    et al.
    Salmela, Elina
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Dahlman-Wright, Karin
    Sistonen, Pertti
    Savontaus, Marja-Liisa
    Schreiber, Stefan
    Lahermo, Päivi
    Kere, Juha
    Genomic landscape of positive natural selection in Northern European populations.2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, no 4, p. 471-478Article in journal (Refereed)
    Abstract [en]

    Analyzing genetic variation of human populations for detecting loci that have been affected by positive natural selection is important for understanding adaptive history and phenotypic variation in humans. In this study, we analyzed recent positive selection in Northern Europe from genome-wide data sets of 250 000 and 500 000 single-nucleotide polymorphisms (SNPs) in a total of 999 individuals from Great Britain, Northern Germany, Eastern and Western Finland, and Sweden. Coalescent simulations were used for demonstrating that the integrated haplotype score (iHS) and long-range haplotype (LRH) statistics have sufficient power in genome-wide data sets of different sample sizes and SNP densities. Furthermore, the behavior of the F(ST) statistic in closely related populations was characterized by allele frequency simulations. In the analysis of the North European data set, 60 regions in the genome showed strong signs of recent positive selection. Out of these, 21 regions have not been discovered in previous scans, and many contain genes with interesting functions (eg, RAB38, INFG, NOS1AP, and APOE). In the putatively selected regions, we observed a statistically significant overrepresentation of genetic association with complex disease, which emphasizes the importance of the analysis of positive selection in understanding the evolution of human disease. Altogether, this study demonstrates the potential of genome-wide data sets to discover loci that lie behind evolutionary adaptation in different human populations.

  • 22. Laskar, Ruhina S
    et al.
    Muller, David C
    Li, Peng
    Machiela, Mitchell J
    Ye, Yuanqing
    Gaborieau, Valerie
    Foll, Matthieu
    Hofmann, Jonathan N
    Colli, Leandro
    Sampson, Joshua N
    Wang, Zhaoming
    Bacq-Daian, Delphine
    Boland, Anne
    Abedi-Ardekani, Behnoush
    Durand, Geoffroy
    Le Calvez-Kelm, Florence
    Robinot, Nivonirina
    Blanche, Helene
    Prokhortchouk, Egor
    Skryabin, Konstantin G
    Burdett, Laurie
    Yeager, Meredith
    Radojevic-Skodric, Sanja
    Savic, Slavisa
    Foretova, Lenka
    Holcatova, Ivana
    Janout, Vladimir
    Mates, Dana
    Rascu, Stefan
    Mukeria, Anush
    Zaridze, David
    Bencko, Vladimir
    Cybulski, Cezary
    Fabianova, Eleonora
    Jinga, Viorel
    Lissowska, Jolanta
    Lubinski, Jan
    Navratilova, Marie
    Rudnai, Peter
    Świątkowska, Beata
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Trichopoulou, Antonia
    Riboli, Elio
    Overvad, Kim
    Panico, Salvatore
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Giles, Graham G
    Milne, Roger L
    Severi, Gianluca
    Bruinsma, Fiona
    Fletcher, Tony
    Koppova, Kvetoslava
    Larsson, Susanna C
    Wolk, Alicja
    Banks, Rosamonde E
    Selby, Peter J
    Easton, Douglas F
    Pharoah, Paul
    Andreotti, Gabriella
    Beane Freeman, Laura E
    Koutros, Stella
    Albanes, Demetrius
    Männistö, Satu
    Weinstein, Stephanie
    Clark, Peter E
    Edwards, Todd L
    Lipworth, Loren
    Carol, Hallie
    Freedman, Matthew L
    Pomerantz, Mark M
    Cho, Eunyoung
    Kraft, Peter
    Preston, Mark A
    Wilson, Kathryn M
    Michael Gaziano, J
    Sesso, Howard D
    Black, Amanda
    Freedman, Neal D
    Huang, Wen-Yi
    Anema, John G
    Kahnoski, Richard J
    Lane, Brian R
    Noyes, Sabrina L
    Petillo, David
    Teh, Bin Tean
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L
    Johnson, Lisa
    Luo, Juhua
    Chow, Wong-Ho
    Moore, Lee E
    Choueiri, Toni K
    Wood, Christopher
    Johansson, Mattias
    McKay, James D
    Brown, Kevin M
    Rothman, Nathaniel
    Lathrop, Mark G
    Deleuze, Jean-Francois
    Wu, Xifeng
    Brennan, Paul
    Chanock, Stephen J
    Purdue, Mark P
    Scelo, Ghislaine
    Sex specific associations in genome wide association analysis of renal cell carcinoma2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 10, p. 1589-1598Article in journal (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

  • 23.
    Mayans, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ruikka, Karin
    Department of Medicine, Sunderby Hospital, Luleå.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Sunderby Hospital, Luleå.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, p. 342-346Article in journal (Refereed)
    Abstract [en]

    A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case-control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case-control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.

  • 24.
    Norberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Raaschou-Jensen, Klas
    Kjeldsen, Lars
    Moilanen, Jukka S.
    Paulsson-Karisson, Ylva
    Baliakas, Panagiotis
    Lohi, Olli
    Ahmed, Aymen
    Kittang, Astrid O.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Novel variants in Nordic patients referred for genetic testing of telomere-related disorders2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed)
    Abstract [en]

    Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

  • 25.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Large-scale parent-child comparison confirms a strong paternal influence on telomere length2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, no 3, p. 385-389Article in journal (Refereed)
    Abstract [en]

    Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent-child pairs in different age groups and between grandparent-grandchild pairs. A highly significant correlation between the father's and the child's telomere length was observed (r=0.454, P<0.001), independent of the sex of the offspring (father-son: r=0.465, P<0.001; father-daughter: r=0.484, P<0.001). For mothers, the correlations were weaker (mother-child: r=0.148, P=0.098; mother-son: r=0.080, P=0.561; mother-daughter: r=0.297, P=0.013). A positive telomere length correlation was also observed for grandparent-grandchild pairs (r=0.272, P=0.013). Our findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers (P=0.012), but we cannot exclude a maternal influence on the daughter's telomeres. Interestingly, the father-child correlations diminished with increasing age (P=0.022), suggesting that nonheritable factors have an impact on telomere length dynamics during life.

  • 26.
    Nääs, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    von Salomé, Jenny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    Patients’ perceptions and practices of informing relatives: a qualitative study within a randomised trial on healthcare-assisted risk disclosure2024In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    In a multicentre randomised controlled trial (DIRECT), we evaluate whether an intervention of providing direct letters from healthcare professionals to at-risk relatives (ARRs) affects the proportion of ARRs contacting a cancer genetics clinic, compared with patient-mediated disclosure alone (control). With the aim to explore how the patients included in the trial perceived and performed risk communication with their ARRs we analysed 17 semi-structured interviews with reflexive thematic analysis. All patients described that they disclosed risk information to all close relatives themselves. No integrity-related issues were reported by patients offered the intervention, and all of them accepted direct letters to all their ARRs. Patients’ approaches to informing distant relatives were unpredictable and varied from contacting all distant ARRs, sharing the burden with the family, utilising the offer of sending direct letters, vaguely relying on others to inform, or postponing disclosure. Most patients limited their responsibility to the disclosure, although others wanted relatives to get genetic counselling or felt a need to provide additional information to the ARRs before ending their mission. We also identified confusion about the implication of test results, who needed risk information, and who was responsible for informing ARRs. These misunderstandings possibly also affected risk disclosure. This study revealed that despite accepting the direct letters to be sent to all relatives, the patients also contributed to risk disclosure in other ways. It was only in some situations to distant relatives that the healthcare-assisted letter was the only means of communication to the ARRs.

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  • 27.
    Pembrey, Marcus E.
    et al.
    Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, England, UK.
    Bygren, Lars Olov
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Biosciences, Preventive Nutrition Karolinska Institute, Karolinska, Sweden.
    Kaati, Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Edvinsson, Sören
    Umeå University, Faculty of Social Sciences, Demographic Data Base.
    Northstone, Kate
    Avon Longitudinal Study of Parents and Children, Bristol University, England, UK.
    Sjöström, Michael
    Department of Biosciences, Preventive Nutrition Karolinska Institute, Karolinska, Sweden.
    Golding, Jean
    Avon Longitudinal Study of Parents and Children, Bristol University, England, UK.
    Sex-specific, male-line transgenerational responses in humans2006In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 14, p. 159-166Article in journal (Refereed)
    Abstract [en]

    Transgenerational effects of maternal nutrition or other environmental 'exposures' are well recognised, but the possibility of exposure in the male influencing development and health in the next generation(s) is rarely considered. However, historical associations of longevity with paternal ancestors' food supply in the slow growth period (SGP) in mid childhood have been reported. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we identified 166 fathers who reported starting smoking before age 11 years and compared the growth of their offspring with those with a later paternal onset of smoking, after correcting for confounders. We analysed food supply effects on offspring and grandchild mortality risk ratios (RR) using 303 probands and their 1818 parents and grandparents from the 1890, 1905 and 1920 Överkalix cohorts, northern Sweden. After appropriate adjustment, early paternal smoking is associated with greater body mass index (BMI) at 9 years in sons, but not daughters. Sex-specific effects were also shown in the Överkalix data; paternal grandfather's food supply was only linked to the mortality RR of grandsons, while paternal grandmother's food supply was only associated with the granddaughters' mortality RR. These transgenerational effects were observed with exposure during the SGP (both grandparents) or fetal/infant life (grandmothers) but not during either grandparent's puberty. We conclude that sex-specific, male-line transgenerational responses exist in humans and hypothesise that these transmissions are mediated by the sex chromosomes, X and Y. Such responses add an entirely new dimension to the study of gene–environment interactions in development and health.

  • 28.
    Rosén, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krajc, Mateja
    Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
    Ehrencrona, Hans
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; Department of Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden.
    Bajalica-Lagercrantz, Svetlana
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Hereditary Cancer Unit, Karolinska University Hospital, Stockholm, Sweden.
    Public attitudes challenge clinical practice on genetic risk disclosure in favour of healthcare-provided direct dissemination to relatives2024In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 32, no 1, p. 6-7Article in journal (Other academic)
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  • 29. Sandling, J. K.
    et al.
    Rosenberg, L. Hultin
    Farias, F. H. G.
    Alexsson, A.
    Leonard, D.
    Kozyrev, S.
    Muren, E.
    Karlsson, A.
    Mathioudaki, A.
    Pucholt, P.
    Eriksson, D.
    Pielberg, G.
    Meadows, J.
    Nordin, J.
    Dahlqvist, J.
    Bianchi, M.
    Bengtsson, Christine
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Jonsen, A.
    Padyukov, L.
    Eloranta, M. L.
    Sjowall, C.
    Gunnarsson, I.
    Svenungsson, E.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Bengtsson, A. A.
    Syvanen, A. C.
    Lindblad-Toh, K.
    Ronnblom, L.
    Targeted next-generation sequencing suggests novel risk loci in juvenile onset systemic lupus erythematosus2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 1372-1373Article in journal (Other academic)
  • 30. Sandling, Johanna K
    et al.
    Garnier, Sophie
    Sigurdsson, Snaevar
    Wang, Chuan
    Nordmark, Gunnel
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A
    Truedsson, Lennart
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mälarstig, Anders
    Strawbridge, Rona J
    Hamsten, Anders
    Criswell, Lindsey A
    Graham, Robert R
    Behrens, Timothy W
    Eloranta, Maija-Leena
    Alm, Gunnar
    Rönnblom, Lars
    Syvänen, Ann-Christine
    A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 4, p. 479-484Article in journal (Refereed)
    Abstract [en]

    Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10(-5)), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.

  • 31. Smith, Bradley N.
    et al.
    Newhouse, Stephen
    Shatunov, Aleksey
    Vance, Caroline
    Topp, Simon
    Johnson, Lauren
    Miller, Jack
    Lee, Younbok
    Troakes, Claire
    Scott, Kirsten M.
    Jones, Ashley
    Gray, Ian
    Wright, Jamie
    Hortobagyi, Tibor
    Al-Sarraj, Safa
    Rogelj, Boris
    Powell, John
    Lupton, Michelle
    Lovestone, Simon
    Sapp, Peter C.
    Weber, Markus
    Nestor, Peter J.
    Schelhaas, Helenius J.
    ten Asbroek, Anneloor A. L. M.
    Silani, Vincenzo
    Gellera, Cinzia
    Taroni, Franco
    Ticozzi, Nicola
    Van den Berg, Leonard
    Veldink, Jan
    Van Damme, Phillip
    Robberecht, Wim
    Shaw, Pamela J.
    Kirby, Janine
    Pall, Hardev
    Morrison, Karen E.
    Morris, Alex
    de Belleroche, Jacqueline
    de Jong, J. M. B. Vianney
    Baas, Frank
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Landers, John
    Brown, Robert H., Jr.
    Weale, Michael E.
    Al-Chalabi, Ammar
    Shaw, Christopher E.
    The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 1, p. 102-108Article in journal (Refereed)
    Abstract [en]

    A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

  • 32.
    van der Crabben, Saskia N.
    et al.
    Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands; European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands.
    Lundström, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands.
    Bikker, Hennie
    Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands; European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands.
    Amin, Ahmad S.
    European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam, Netherlands.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands.
    Wilde, Arthur A. M.
    European Reference Network for rare, low-prevalence, or complex diseases of the heart (ERN GUARD-Heart), Amsterdam, Netherlands; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam, Netherlands.
    Should variants of unknown significance (VUS) be disclosed to patients in cardiogenetics or not; only in case of high suspicion of pathogenicity?2022In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 30, p. 1208-1210Article in journal (Refereed)
  • 33. Wang, Chuan
    et al.
    Ahlford, Annika
    Järvinen, Tiina M
    Nordmark, Gunnel
    Eloranta, Maija-Leena
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A
    Truedsson, Lennart
    Eriksson, Catharina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sjöwall, Christopher
    Julkunen, Heikki
    Criswell, Lindsey A
    Graham, Robert R
    Behrens, Timothy W
    Kere, Juha
    Rönnblom, Lars
    Syvänen, Ann-Christine
    Sandling, Johanna K
    Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 9, p. 994-999Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case-control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

  • 34. Wentzel, Christian
    et al.
    Rajcan-Separovic, Evica
    Ruivenkamp, Claudia A L
    Chantot-Bastaraud, Sandra
    Metay, Corinne
    Andrieux, Joris
    Annerén, Göran
    Gijsbers, Antoinet C J
    Druart, Luc
    Hyon, Capucine
    Portnoi, Marie-France
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Vincent-Delorme, Catherine
    Kant, Sarina G
    Steinraths, Michelle
    Marlin, Sandrine
    Giurgea, Irina
    Thuresson, Ann-Charlotte
    Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p112011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 9, p. 959-964Article in journal (Refereed)
    Abstract [en]

    With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

  • 35.
    Öfverholm, Anna
    et al.
    Institute of Clinical Sciences, Department of Oncology, Sahlgrenska Academy, Gothenburg University, Göteborg, Sweden.
    Karlsson, Per
    Institute of Clinical Sciences, Department of Oncology, Sahlgrenska Academy, Gothenburg University, Göteborg, Sweden.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention.
    The experience of receiving a letter from a cancer genetics clinic about risk for hereditary cancer2024In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    Direct contact may be an option for supporting disclosure in families with hereditary cancer risk. In this qualitative interview study, we explored how healthy at-risk relatives experience receiving a letter with information about hereditary cancer directly from healthcare rather than via a relative. The study is part of an ongoing multicentre randomised clinical trial in Sweden that evaluates the effectiveness of direct letters from cancer genetics clinics to at-risk relatives. After conducting semi-structured interviews with 14 relatives who had received a letter and contacted the clinic, we analysed the data using thematic analysis. The relatives had different levels of prior knowledge about the hereditary cancer assessment. Many had been notified by family that a letter was coming but some had not. Overall, these participants believed healthcare-mediated disclosure could complement family-mediated disclosure. They expressed that the letter and the message raised concerns and a need for counselling, and they wanted healthcare to be accessible and informed when making contact. The participants found the message easier to cope with when they had been notified by a family member beforehand, with a general attitude that notifying relatives was the appropriate step to take. They thought healthcare should help patients with the disclosure process but also guard the right of at-risk relatives to be informed. The findings support a direct approach from healthcare as a possible complement to an established model of family-mediated risk disclosure, but implementation must be made within existing frameworks of good practice for genetic counselling.

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