Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey

Spracklen, Cassandra N.; Shi, Jianxin; Vadlamudi, Swarooparani; Wu, Ying; Zou, Meng; Raulerson, Chelsea K.; Davis, James P.; Zeynalzadeh, Monica; Jackson, Kayla; Yuan, Wentao; Wang, Haifeng; Shou, Weihua; Wang, Ying; Luo, Jingchun; Lange, Leslie A.; Lange, Ethan M.; Popkin, Barry M.; Gordon‐Larsen, Penny; Du, Shufa; Huang, Wei; Mohlke, Karen L.

doi:10.1371/journal.pgen.1007275

Cited by 32 publications

(27 citation statements)

References 83 publications

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“…Furthermore, more than 200 SNPs were found to reach the level of a suggestive association. We compared our results with previously reported SNPs [ 25 – 27 , 37 – 40 ] and found that 8 SNPs could be replicated, indicating our results were credible.…”

Section: Discussionsupporting

confidence: 57%

Heritability and genome-wide association analyses of fasting plasma glucose in Chinese adult twins

et al. 2020

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Background: Currently, diabetes has become one of the leading causes of death worldwide. Fasting plasma glucose (FPG) levels that are higher than optimal, even if below the diagnostic threshold of diabetes, can also lead to increased morbidity and mortality. Here we intend to study the magnitude of the genetic influence on FPG variation by conducting structural equation modelling analysis and to further identify specific genetic variants potentially related to FPG levels by performing a genome-wide association study (GWAS) in Chinese twins. Results: The final sample included 382 twin pairs: 139 dizygotic (DZ) pairs and 243 monozygotic (MZ) pairs. The DZ twin correlation for the FPG level (r DZ = 0.20, 95% CI: 0.04-0.36) was much lower than half that of the MZ twin correlation (r MZ = 0.68, 95% CI: 0.62-0.74). For the variation in FPG level, the AE model was the better fitting model, with additive genetic parameters (A) accounting for 67.66% (95% CI: 60.50-73.62%) and unique environmental or residual parameters (E) accounting for 32.34% (95% CI: 26.38-39.55%), respectively. In the GWAS, although no genetic variants reached the genome-wide significance level (P < 5 × 10 − 8), 28 SNPs exceeded the level of a suggestive association (P < 1 × 10 − 5). One promising genetic region (2q33.1) around rs10931893 (P = 1.53 × 10 − 7) was found. After imputing untyped SNPs, we found that rs60106404 (P = 2.38 × 10 − 8) located at SPATS2L reached the genome-wide significance level, and 216 SNPs exceeded the level of a suggestive association. We found 1007 genes nominally associated with the FPG level (P < 0.05), including SPATS2L, KCNK5, ADCY5, PCSK1, PTPRA, and SLC26A11. Moreover, C1orf74 (P = 0.014) and SLC26A11 (P = 0.021) were differentially expressed between patients with impaired fasting glucose and healthy controls. Some important enriched biological pathways, such as βalanine metabolism, regulation of insulin secretion, glucagon signaling in metabolic regulation, IL-1 receptor pathway, signaling by platelet derived growth factor, cysteine and methionine metabolism pathway, were identified.

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Section: Discussionsupporting

confidence: 57%

Heritability and genome-wide association analyses of fasting plasma glucose in Chinese adult twins

et al. 2020

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“…Within the East Asian meta-analysis, the direction of effect is consistent across East Asian countries ( Extended Data Figure 9B ) and within the contributing cohorts ( Extended Data Figure 9C ). The T2D risk allele rs12712928-C is associated with higher fasting glucose levels in East Asian populations, has the strongest association with lower expression levels of both SIX3 and SIX2 in pancreatic islets 19 , and demonstrated allele-specific binding to the transcription factor GABPA and significantly lower levels of transcriptional activity 36 . While rs12712928-C is present on only one common haplotype in most populations, it is present on an additional common haplotype (frequency =0.075) in East Asians, suggesting that the effect size attributed to rs12712928 may be influenced by other nearby unknown variants.…”

Section: Resultsmentioning

confidence: 99%

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Spracklen

Horikoshi

Kim

et al. 2020

Nature

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SUMMARY Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D) 1 , 2 , however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1 , PTF1A , SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation 3 . At another locus, eQTLs at two overlapping T2D signals affect two genes, NKX6-3 and ANK1 , in different tissues 4 – 6 . Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.

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“…As such, understanding the genetic predisposition to particular phenotype measurements, and the factors that confound them, has implications for disease treatment. While the genetics of some biomarkers have been extensively studied, most notably lipids 1 , 2,3 , glycaemic traits [4][5][6] , and measurements of kidney function [7][8][9] , most biomarkers have only had limited measured genetic contribution.…”

Section: Introductionmentioning

confidence: 99%

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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Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey

Cited by 32 publications

References 83 publications

Heritability and genome-wide association analyses of fasting plasma glucose in Chinese adult twins

Heritability and genome-wide association analyses of fasting plasma glucose in Chinese adult twins

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Genetics of 38 blood and urine biomarkers in the UK Biobank

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