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Sökning: WFRF:(Stefansson Hreinn)

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1.
  • Njølstad, Pål Rasmus, et al. (författare)
  • Roadmap for a precision-medicine initiative in the Nordic region
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718.
  • Tidskriftsartikel (refereegranskat)abstract
    • The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.
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2.
  • Sonderby, Ida E., et al. (författare)
  • Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
  • 2020
  • Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
  • Tidskriftsartikel (refereegranskat)abstract
    • Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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3.
  • van der Meer, Dennis, et al. (författare)
  • Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition
  • 2020
  • Ingår i: JAMA psychiatry. - 2168-6238 .- 2168-622X. ; 77:4, s. 420-430
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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4.
  • de Jong, Simone, et al. (författare)
  • Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
  • 2018
  • Ingår i: Communications Biology. - : Nature Publishing Group. - 2399-3642. ; 1
  • Tidskriftsartikel (refereegranskat)abstract
    • Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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5.
  • Gretarsdottir, Solveig, et al. (författare)
  • Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm
  • 2010
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 42:8, s. 71-692
  • Tidskriftsartikel (refereegranskat)abstract
    • We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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6.
  • Helgadottir, Anna, et al. (författare)
  • The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm
  • 2008
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 40:2, s. 217-224
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD)(1-4) and type 2 diabetes (T2D)(5-7), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.
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8.
  • Olafsson, Sigurgeir, et al. (författare)
  • Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
  • Ingår i: npj Genomic Medicine. - : Nature Publishing Group. - 2056-7944. ; 2:1
  • Tidskriftsartikel (refereegranskat)abstract
    • A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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10.
  • Ripke, Stephan, et al. (författare)
  • Biological insights from 108 schizophrenia-associated genetic loci
  • 2014
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 511:7510, s. 421-427
  • Tidskriftsartikel (refereegranskat)abstract
    • Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
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