scholarly journals Carotid intima-media thickness in UK Biobank: Identification of novel genome-wide loci, sex-specific effects and genetic correlations with obesity and glucometabolic traits

2019 ◽  
Author(s):  
Rona J. Strawbridge ◽  
Joey Ward ◽  
Mark E.S. Bailey ◽  
Breda Cullen ◽  
Amy Ferguson ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Association Studies ◽  
Genetic Correlations ◽  
Intima Media Thickness ◽  
Genome Wide Association ◽  
Ultra Sound ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Media Thickness ◽  
Genome Wide

AbstractObjectivesAtherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultra-sound measurement of the carotid artery intima-media thickness (cIMT) can be used to measure vascular remodelling, which is indicative of atherosclerosis. Genome-wide association studies have identified a number of genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here we conducted genome-wide association analyses in UK Biobank (N=22,179), the largest single study with consistent cIMT measurements.Approach and resultsWe used BOLT-LMM to run linear regression of cIMT in UK Biobank, adjusted for age, sex, genotyping platform and population structure. In white British participants, we identified 4 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a female-specific locus on Chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body-mass index and glucometabolic traits were also observed.ConclusionThese findings replicate previously reported associations, highlight novel biology and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

scholarly journals Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals

2021 ◽  
Author(s):  
Ming Wai Yeung ◽  
Siqi Wang ◽  
Yordi J. van de Vegte ◽  
Oleg Borisov ◽  
Jessica van Setten ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Intima Media Thickness ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Susceptibility Loci ◽  
Media Thickness ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P <5×10 −8 . Seven novel loci ( ZNF385D , AD AMTS9 , EDNRA , HAND2 , MYOCD , ITCH/EDEM2/ matrix metalloproteinase [ MMP ] 24 , and MRTFA ) were identified in all 3 phenotypes. An additional new locus ( LOXL1 ) was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus ( SYNE3 ) in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci ( APOB, FIP1L1, and LOXL4 ). Transcriptome-wide association analyses implicated additional genes ARHGAP42 , NDRG4 , and KANK2 . Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease r g =0.21 ( P =1.4×10 -7 ), peripheral artery disease r g =0.45 ( P =5.3×10 -5 ), and systolic blood pressure r g =0.30 ( P =4.0×10 -18 ). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found r g =−0.12 ( P =7.0×10 -4 ). Conclusions: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.

scholarly journals GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

2020 ◽  
Author(s):  
Nasa Sinnott-Armstrong ◽  
Sahin Naqvi ◽  
Manuel Rivas ◽  
Jonathan K Pritchard
Keyword(s):  
Complex Traits ◽  
Genetic Basis ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Uk Biobank ◽  
The Core ◽  
Genome Wide ◽  
Core Genes

SummaryGenome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. However, for most traits it remains difficult to interpret what genes and biological processes are impacted by the top hits. Here, as a contrast, we describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—that are biologically simpler than most diseases, and for which we know a great deal in advance about the core genes and pathways. Unlike most GWAS of complex traits, for all three traits we find that most top hits are readily interpretable. We observe huge enrichment of significant signals near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of variation in each trait, including insights into differences in testosterone regulation between females and males. Meanwhile, in other respects the results are reminiscent of GWAS for more-complex traits. In particular, even these molecular traits are highly polygenic, with most of the variance coming not from core genes, but from thousands to tens of thousands of variants spread across most of the genome. Given that diseases are often impacted by many distinct biological processes, including these three, our results help to illustrate why so many variants can affect risk for any given disease.

scholarly journals Reproducibility in the UK Biobank of Genome-Wide Significant Signals Discovered in Earlier Genome-wide Association Studies

2020 ◽  
Author(s):  
Jack W. O’Sullivan ◽  
John P. A. Ioannidis
Keyword(s):  
Effect Size ◽  
Association Studies ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Single Nucleotide ◽  
Genome Wide ◽  
The Uk ◽  
Open Question

AbstractWith the establishment of large biobanks, discovery of single nucleotide polymorphism (SNPs) that are associated with various phenotypes has been accelerated. An open question is whether SNPs identified with genome-wide significance in earlier genome-wide association studies (GWAS) are replicated also in later GWAS conducted in biobanks. To address this question, the authors examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, replication GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNPs (of which 6,289 had reached p<5e-8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0% and it was lower for binary than for quantitative phenotypes (58.1% versus 94.8% respectively). There was a18.0% decrease in SNP effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNP effect size, phenotype trait (binary or quantitative), and discovery p-value, we built and validated a model that predicted SNP replication with area under the Receiver Operator Curve = 0.90. While non-replication may often reflect lack of power rather than genuine false-positive findings, these results provide insights about which discovered associations are likely to be seen again across subsequent GWAS.

scholarly journals Insights into the genetic basis of retinal detachment

2019 ◽  
Vol 29 (4) ◽  
pp. 689-702 ◽  
Author(s):  
Thibaud S Boutin ◽  
David G Charteris ◽  
Aman Chandra ◽  
Susan Campbell ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Association Studies ◽  
Genetic Correlations ◽  
Self Report ◽  
Cataract Operation ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Data Set ◽  
Genome Wide

Abstract Retinal detachment (RD) is a serious and common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. In the UK Biobank data set, where RD was ascertained by self-report or hospital records, genetic correlations between RD and high myopia or cataract operation were, respectively, 0.46 (SE = 0.08) and 0.44 (SE = 0.07). These correlations are consistent with known epidemiological associations. Through meta-analysis of genome-wide association studies using UK Biobank RD cases (N = 3 977) and two cohorts, each comprising ~1 000 clinically ascertained rhegmatogenous RD patients, we uncovered 11 genome-wide significant association signals. These are near or within ZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1 and LOXL1. Replication in the 23andMe data set, where RD is self-reported by participants, firmly establishes six RD risk loci: FAT3, COL22A1, TYR, BMP3, ZC3H11B and PLCE1. Based on the genetic associations with eye traits described to date, the first two specifically impact risk of a RD, whereas the last four point to shared aetiologies with macular condition, myopia and glaucoma. Fine-mapping prioritized the lead common missense variant (TYR S192Y) as causal variant at the TYR locus and a small set of credible causal variants at the FAT3 locus. The larger study size presented here, enabled by resources linked to health records or self-report, provides novel insights into RD aetiology and underlying pathological pathways.

scholarly journals A combined analysis of genetically correlated traits identifies 107 loci associated with intelligence

2017 ◽  
Author(s):  
W. D. Hill ◽  
G. Davies ◽  
A. M. McIntosh ◽  
C. R. Gale ◽  
I. J. Deary
Keyword(s):  
Household Income ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Correlated Traits ◽  
Single Measure ◽  
Combined Analysis ◽  
Genome Wide

AbstractIntelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including many physical and mental health variables. Both education and household income are strongly genetically correlated with intelligence, at rg =0.73 and rg =0.70 respectively. This allowed us to utilize a novel approach, Multi-Trait Analysis of Genome-wide association studies (MTAG; Turley et al. 2017), to combine two large genome-wide association studies (GWASs) of education and household income to increase power in the largest GWAS on intelligence so far (Sniekers et al. 2017). This study had four goals: firstly, to facilitate the discovery of new genetic loci associated with intelligence; secondly, to add to our understanding of the biology of intelligence differences; thirdly, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predict phenotypic intelligence variance in an independent sample. We apply MTAG to three large GWAS: Sniekers et al (2017) on intelligence, Okbay et al. (2016) on Educational attainment, and Hill et al. (2016) on household income. By combining these three samples our functional sample size increased from 78 308 participants to 147 194. We found 107 independent loci associated with intelligence, implicating 233 genes, using both SNP-based and gene-based GWAS. We find evidence that neurogenesis may explain some of the biological differences in intelligence as well as genes expressed in the synapse and those involved in the regulation of the nervous system. We show that the results of our combined analysis demonstrate the same pattern of genetic correlations as a single measure/the simple measure of intelligence, providing support for the meta-analysis of these genetically-related phenotypes. We find that our MTAG meta-analysis of intelligence shows similar genetic correlations to 26 other phenotypes when compared with a GWAS consisting solely of cognitive tests. Finally, using an independent sample of 6 844 individuals we were able to predict 7% of intelligence using SNP data alone.

scholarly journals The evolution of skin pigmentation associated variation in West Eurasia

2020 ◽  
Author(s):  
Dan Ju ◽  
Iain Mathieson
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Skin Pigmentation ◽  
Directional Selection ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Light Skin ◽  
The Uk

AbstractSkin pigmentation is a classic example of a polygenic trait that has experienced directional selection in humans. Genome-wide association studies have identified well over a hundred pigmentation-associated loci, and genomic scans in present-day and ancient populations have identified selective sweeps for a small number of light pigmentation-associated alleles in Europeans. It is unclear whether selection has operated on all the genetic variation associated with skin pigmentation as opposed to just a small number of large-effect variants. Here, we address this question using ancient DNA from 1158 individuals from West Eurasia covering a period of 40,000 years combined with genome-wide association summary statistics from the UK Biobank. We find a robust signal of directional selection in ancient West Eurasians on skin pigmentation variants ascertained in the UK Biobank, but find this signal is driven mostly by a limited number of large-effect variants. Consistent with this observation, we find that a polygenic selection test in present-day populations fails to detect selection with the full set of variants; rather, only the top five show strong evidence of selection. Our data allow us to disentangle the effects of admixture and selection. Most notably, a large-effect variant at SLC24A5 was introduced to Europe by migrations of Neolithic farming populations but continued to be under selection post-admixture. This study shows that the response to selection for light skin pigmentation in West Eurasia was driven by a relatively small proportion of the variants that are associated with present-day phenotypic variation.SignificanceSome of the genes responsible for the evolution of light skin pigmentation in Europeans show signals of positive selection in present-day populations. Recently, genome-wide association studies have highlighted the highly polygenic nature of skin pigmentation. It is unclear whether selection has operated on all of these genetic variants or just a subset. By studying variation in over a thousand ancient genomes from West Eurasia covering 40,000 years we are able to study both the aggregate behavior of pigmentation-associated variants and the evolutionary history of individual variants. We find that the evolution of light skin pigmentation in Europeans was driven by frequency changes in a relatively small fraction of the genetic variants that are associated with variation in the trait today.

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