| 1. |
- Cesarini, David, et al.
(författare)
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Genotype-covariate interaction effects and the heritability of adult body mass index
- 2017
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 49:8, s. 1174-1181
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 × 10-18), which contributed 8.1% (1.4% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype-environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 × 10-5 and LRT = 30.80, P = 1.42 × 10-8), which contributed 4.0% (0.8% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI.
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| 2. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 3. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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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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| 4. |
- Lee, James J, et al.
(författare)
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
- 2018
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:8, s. 1112-1121
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Tidskriftsartikel (refereegranskat)abstract
- Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1million individuals and identify 1,271independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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| 5. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 6. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 7. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 8. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 9. |
- Tasa, Tonis, et al.
(författare)
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Genetic variation in the Estonian population : pharmacogenomics study of adverse drug effects using electronic health records
- 2019
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Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 27:3, s. 442-454
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel lossof-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.
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| 10. |
- Zhou, Yitian, et al.
(författare)
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Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk
- 2018
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Ingår i: Journal of Lipid Research. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0022-2275 .- 1539-7262. ; 59:10, s. 1987-2000
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identify further 6,875 genetic variants, 33% of which are novel and 98.7% of which are rare with minor allele frequencies <1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM (Coronary Artery Disease Genomewide Replication and Meta-analysis) and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits, and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.
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