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Sökning: WFRF:(Giddaluru S) > Giddaluru S

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  • Davies, G., et al. (författare)
  • Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
  • 2018
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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  • Davies, G., et al. (författare)
  • Genetic contributions to variation in general cognitive function : a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
  • 2015
  • Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 20:2, s. 183-192
  • Tidskriftsartikel (refereegranskat)abstract
    • General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health-and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N = 53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P = 3.93 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N = 6617) and the Health and Retirement Study (N = 5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e. = 5%) and 28% (s.e. = 7%), respectively. Using polygenic prediction analysis, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
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  • Witoelar, A, et al. (författare)
  • Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci
  • 2018
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 18088-
  • Tidskriftsartikel (refereegranskat)abstract
    • A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10−6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.
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  • Athanasiu, L., et al. (författare)
  • A genetic association study of CSMD1 and CSMD2 with cognitive function
  • 2017
  • Ingår i: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 61, s. 209-216
  • Tidskriftsartikel (refereegranskat)abstract
    • The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease. (C) 2016 The Authors. Published by Elsevier Inc.
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  • Howe, LJ, et al. (författare)
  • Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
  • 2022
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:65, s. 581-
  • Tidskriftsartikel (refereegranskat)abstract
    • Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
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  • Stokowy, T, et al. (författare)
  • Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes
  • 2018
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 6915-
  • Tidskriftsartikel (refereegranskat)abstract
    • Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We established a set of 117 myelination genes by database searches and manual curation. We used a combination of GWAS (SCZ_N = 35,476; CTRL_N = 46,839), exome chip (SCZ_N = 269; CTRL_N = 336) and exome sequencing data (SCZ_N = 2,527; CTRL_N = 2,536) from schizophrenia cases and healthy controls to examine common and rare variants. We found that a subset of lipid-related genes was nominally associated with schizophrenia (p = 0.037), but this signal did not survive multiple testing correction (FWER = 0.16) and was mainly driven by the SREBF1 and SREBF2 genes that have already been linked to schizophrenia. Further analysis demonstrated that the lowest nominal p-values were p = 0.0018 for a single common variant (rs8539) and p = 0.012 for burden of rare variants (LRP1 gene), but none of them survived multiple testing correction. Our findings suggest that variation in myelination-related genes is not a major risk factor for schizophrenia.
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