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Sökning: WFRF:(McCarroll Steven A.)

  • Resultat 11-17 av 17
  • Föregående 1[2]
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11.
  • Jia, Xiaoming, et al. (författare)
  • Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
  • 2021
  • Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578.
  • Tidskriftsartikel (refereegranskat)abstract
    • Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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12.
  • Genovese, Giulio, et al. (författare)
  • Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
  • 2014
  • Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 371:26, s. 2477-87
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
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13.
  • Thompson, Deborah J, et al. (författare)
  • Genetic predisposition to mosaic Y chromosome loss in blood
  • 2019
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 575, s. 652-657
  • Tidskriftsartikel (refereegranskat)abstract
    • Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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14.
  • Willer, Cristen J., et al. (författare)
  • Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
  • 2009
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 41:1, s. 25-34
  • Tidskriftsartikel (refereegranskat)abstract
    • Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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15.
  • McCarroll, Steven A, et al. (författare)
  • Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease
  • 2008
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 40:9, s. 1107-1112
  • Tidskriftsartikel (refereegranskat)abstract
    • Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
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16.
  • McCarthy, Shane, et al. (författare)
  • A reference panel of 64,976 haplotypes for genotype imputation
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; 48:10, s. 1279-1283
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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17.
  • Szatkiewicz, Jin, et al. (författare)
  • The genomics of major psychiatric disorders in a large pedigree from Northern Sweden
  • 2019
  • Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188 .- 2158-3188. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.
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  • Resultat 11-17 av 17
  • Föregående 1[2]
 
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