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1.
  • Karlsson Linnér, Richard, et al. (författare)
  • Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences
  • 2019
  • Ingår i: Nature genetics. - 1546-1718. ; 51:2, s. 245-
  • Tidskriftsartikel (refereegranskat)abstract
    • Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (vertical bar(r) over cap (g)vertical bar similar to 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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2.
  • Huckins, Laura M., et al. (författare)
  • Gene expression imputation across multiple brain regions provides insights into schizophrenia risk
  • 2019
  • Ingår i: Nature genetics. - 1546-1718. ; 51:4, s. 659-
  • Tidskriftsartikel (refereegranskat)abstract
    • Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
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3.
  • Sung, Yun J., et al. (författare)
  • A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure
  • 2018
  • Ingår i: American Journal of Human Genetics. - 0002-9297. ; 102:3, s. 375-400
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).
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4.
  • Bentley, Amy R., et al. (författare)
  • Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids
  • 2019
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036. ; 51:4, s. 636-
  • Tidskriftsartikel (refereegranskat)abstract
    • The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
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5.
  • Ligthart, Symen, et al. (författare)
  • Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
  • 2018
  • Ingår i: American Journal of Human Genetics. ; 103:5, s. 691-706
  • Tidskriftsartikel (refereegranskat)abstract
    • C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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6.
  • Perry, John R. B., et al. (författare)
  • Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche
  • 2014
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 514:7520, s. 92-
  • Tidskriftsartikel (refereegranskat)abstract
    • Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
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7.
  • Wuttke, Matthias, et al. (författare)
  • A catalog of genetic loci associated with kidney function from analyses of a million individuals
  • 2019
  • Ingår i: Nature Genetics. - NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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8.
  • Feitosa, Mary F., et al. (författare)
  • Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
  • 2018
  • Ingår i: PLoS ONE. - Public library science. - 1932-6203. ; 13:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
9.
  • Joshi, Peter K, et al. (författare)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • Tidskriftsartikel (refereegranskat)abstract
    • Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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10.
  • Kilpeläinen, Tuomas O, et al. (författare)
  • Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
  • 2019
  • Ingår i: Nature Communications. - London : Nature Publishing Group. - 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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