Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease

Lu, Xiangfeng; Peloso, Gina M.; Liu, Dajiang; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara S.; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N.; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea‐Chuen; Li, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu‐Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jianxin; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H‐H; Cherny, Stacey S.; He, Meian; Feranil, Alan B.; Adair, Linda S.; Gordon‐Larsen, Penny; Du, Shufa; Varma, Rohit; Chen, Yii‐Der Ida; Shu, Xiao‐Ou; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K.; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars G.; Jb, Nielsen; Tse, Hung‐Fat; Huo, Yong; Cheng, Ching‐Yu; Chen, Y Eugene; Wang, Zheng; Tai, E. Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Gonçalo R.; Kathiresan, Sekar; Mohlke, Karen L.; Wu, Tangchun; Sham, Pak C.; Gu, Dongfeng; Willer, Cristen J.

doi:10.1038/ng.3978

Cited by 126 publications

(116 citation statements)

References 40 publications

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“…Several studies have demonstrated the association between ChREBP gene polymorphisms and plasma TG levels or glucose‐related traits . Recently, a functional coding variant in ChREBP (rs35332062) was identified in both East Asian and European populations with similar MAF (0.117 in East Asian and 0.109 in European populations, respectively) . However, only the rs1051943 A allele was found in our study population, which was different from the European population (rs1051943 MAF = 0.07).…”

Section: Discussioncontrasting

confidence: 71%

miR‐1322 regulates ChREBP expression via binding a 3′‐UTR variant (rs1051943)

Zhang

et al. 2018

J Cellular Molecular Medi

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The carbohydrate response element‐binding protein (ChREBP), also referred to as MLXIPL, plays a crucial role in the regulation of glucose and lipid metabolism. Existing studies have shown an association between genetic variations of the ChREBP gene and lipid levels, such as triglycerides and high‐density lipoprotein cholesterol. However, mechanistic studies of this association are limited. In this study, bioinformatic analysis revealed that the polymorphism rs1051943A occurs in the complementary binding sequence of miR‐1322 in the ChREBP 3′‐untranslated region (UTR). Studies of potential mechanisms showed that the A allele could facilitate miR‐1322 binding, and luciferase activity significantly decreased when co‐transfected with a ChREBP 3′‐UTR luciferase reporter vector and miR‐1322 mimics in HepG2 cells. Furthermore, miR‐1322 significantly regulated the expression of ChREBP downstream genes and reduced the synthesis of lipids. The expression of miR‐1322 was up‐regulated by glucose and palmitic acid stimulation. Population studies showed that rs1051943‐A allele was only found in the Han Chinese and Uighur ethnic groups, different from European populations (G allele frequency = 0.07). In summary, we provide evidence that the rs1051943 A allele creates a functional miR‐1322 binding site in ChREBP 3′‐UTR and post‐transcriptionally down‐regulates its expression, possibly associated with levels of plasma lipids and glucose.

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Section: Discussioncontrasting

confidence: 71%

miR‐1322 regulates ChREBP expression via binding a 3′‐UTR variant (rs1051943)

Zhang

et al. 2018

J Cellular Molecular Medi

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“…We performed association analysis between autosomal genetic variants and 38 biomarkers in 318,984 unrelated selfidentifiedWhiteBritish individuals of European ancestry and stratified the association into three bins: 1) proteintruncating (27,816), 2) proteinaltering (87,407), and 3) noncoding (MAF > 1%, 1000 Genomes Phase 1 variants also present in Haplotype Reference Consortium [HRC], 9,444,561 17 ) ( Figure 2A ). Comparison of effect sizes estimated across 42 comparison studies with 25 of the biomarkers show overall high agreement (correlation greater than 0.5 for 33 comparisons, Supplementary Figure 5 , Supplementary Table 4 for comparison) across previous studies of lipids 1,2,18,19 , glycaemic 20 , 21 , kidney function 22,23 , liver function 20 , and other biomarkers measurements 24,25 .…”

Section: Genetics Of Biomarkerssupporting

confidence: 54%

Genetics of 38 blood and urine biomarkers in the UK Biobank

Sinnott-Armstrong

Tanigawa

Amar

et al. 2019

Preprint

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Clinical laboratory tests are a critical component of the continuum of care and provide a means for rapid diagnosis and monitoring of chronic disease. In this study, we systematically evaluated the genetic basis of 38 blood and urine laboratory tests measured in 358,072 participants in the UK Biobank and identified 1,857 independent loci associated with at least one laboratory test, including 488 largeeffect protein truncating, missense, and copynumber variants. We tested these loci for enrichment in specific single cell types in kidney, liver, and pancreas relevant to disease aetiology. We then causally linked the biomarkers to medically relevant phenotypes through genetic correlation and Mendelian randomization. Finally, we developed polygenic risk scores (PRS) for each biomarker and built multiPRS models using all 38 PRSs simultaneously. We found substantially improved prediction of incidence in FinnGen (n=135,500) with the multiPRS relative to singledisease PRSs for renal failure, myocardial infarction, liver fat percentage, and alcoholic cirrhosis. Together, our results show the genetic basis of these biomarkers, which tissues contribute to the biomarker function, the causal influences of the biomarkers, and how we can use this to predict disease. 45 50 55 60 65 70 75 80 85 90 95 100

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“…Notably, most of the dyslipidemia genes are also linked to GWAS signals, indicating that common variants at these loci also contribute to lipid levels [56,57,58,38,59]. For example, 7 out of 10 genes associated with monogenic disorders of LDL-cholesterol levels are within the set of 57 genome-wide significant hit regions from a GWAS of LDL levels [20,57].…”

Section: Discussionmentioning

confidence: 99%

Trans effects on gene expression can drive omnigenic inheritance

Liu

Pritchard

2018

Preprint

145

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Early genome-wide association studies (GWAS) led to the surprising discovery that, for typical complex traits, the most significant genetic variants contribute only a small fraction of the estimated heritability. Instead, it has become clear that a huge number of common variants, each with tiny effects, explain most of the heritability. Previously, we argued that these patterns conflict with standard conceptual models, and that new models are needed. Here we provide a formal model in which genetic contributions to complex traits can be partitioned into direct effects from core genes, and indirect effects from peripheral genes acting as trans-regulators. We argue that the central importance of peripheral genes is a direct consequence of the large contribution of trans-acting variation to gene expression variation. In particular, we propose that if the core genes for a trait are co-regulated -as seems likely -then the effects of peripheral variation can be amplified by these co-regulated networks such that nearly all of the genetic variance is driven by peripheral genes. Thus our model proposes a framework for understanding key features of the architecture of complex traits.Key observations. As reviewed in our previous paper [10], a conceptual model of complex traits should allow for the following observations:

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Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants that contribute to lipid levels and coronary artery disease

Cited by 126 publications

References 40 publications

miR‐1322 regulates ChREBP expression via binding a 3′‐UTR variant (rs1051943)

miR‐1322 regulates ChREBP expression via binding a 3′‐UTR variant (rs1051943)

Genetics of 38 blood and urine biomarkers in the UK Biobank

Trans effects on gene expression can drive omnigenic inheritance

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