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A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans.

Li H, Gan W, Lu L, Dong X, Han X, Hu C, Yang Z, Sun L, Bao W, Li P, He M, Sun L, Wang Y, Zhu J, Ning Q, Tang Y, Zhang R, Wen J, Wang D, Zhu X, Guo K, Zuo X, Guo X, Yang H, Zhou X, DIAGRAM ConsortiumAGEN-T2D ConsortiumZhang X, Qi L, Loos RJ, Hu FB, Wu T, Liu Y, Liu L, Yang Z, Hu R, Jia W, Ji L, Li Y, Lin X - Diabetes (2012)

Bottom Line: Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians.In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose.Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

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Manhattan plot for genome-wide association analysis of 495,686 genotyped SNPs in stage 1. The −log10P values were from pooled analysis, adjusting for age, sex, and the first two principle components. The red dots at each locus indicate the signals with P < 10−6.
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Figure 2: Manhattan plot for genome-wide association analysis of 495,686 genotyped SNPs in stage 1. The −log10P values were from pooled analysis, adjusting for age, sex, and the first two principle components. The red dots at each locus indicate the signals with P < 10−6.

Mentions: In stage 1, we tested the association with T2D of 2,234,194 genotyped and imputed SNPs that passed all QC criteria in 3,712 Chinese Hans from Beijing and Shanghai, of which 1,839 were case subjects, and 1,873 were control subjects. No significant population stratification was observed between case and control subjects using principle component analysis (Supplementary Fig. 2), and the genomic control factor was also quite close to 1.0 (λ = 1.03), suggesting there is no genome-wide inflation due to population stratification for stage 1 samples. The quantile–quantile plot showed substantial deviation from the expected at the lower P values, suggesting that some associations were more significant than expected by chance (Supplementary Fig. 3). SNPs in four previously reported T2D loci (CDKAL1, CDKN2A/B, KCNQ1, and DUSP9) reached genome-wide significance (P < 5 × 10−8) (Fig. 2 and Supplementary Fig. 4), with directional consistency as previously reported (21–25). For the other previously reported T2D loci, apart from three loci that were monomorphic in Chinese Hans, 48 of 51 loci showed directionally consistent association with T2D (binomial test, P = 9.8 × 10−12), of which 19 were associated with T2D at P < 0.05 (Supplementary Table 3). Of these, only the rs7754840 in CDKAL1 showed a significantly larger effect on T2D in Chinese Hans than in white Europeans (P for heterogeneity = 3.33 × 10−4), consistent with our previous findings (26).


A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans.

Li H, Gan W, Lu L, Dong X, Han X, Hu C, Yang Z, Sun L, Bao W, Li P, He M, Sun L, Wang Y, Zhu J, Ning Q, Tang Y, Zhang R, Wen J, Wang D, Zhu X, Guo K, Zuo X, Guo X, Yang H, Zhou X, DIAGRAM ConsortiumAGEN-T2D ConsortiumZhang X, Qi L, Loos RJ, Hu FB, Wu T, Liu Y, Liu L, Yang Z, Hu R, Jia W, Ji L, Li Y, Lin X - Diabetes (2012)

Manhattan plot for genome-wide association analysis of 495,686 genotyped SNPs in stage 1. The −log10P values were from pooled analysis, adjusting for age, sex, and the first two principle components. The red dots at each locus indicate the signals with P < 10−6.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526061&req=5

Figure 2: Manhattan plot for genome-wide association analysis of 495,686 genotyped SNPs in stage 1. The −log10P values were from pooled analysis, adjusting for age, sex, and the first two principle components. The red dots at each locus indicate the signals with P < 10−6.
Mentions: In stage 1, we tested the association with T2D of 2,234,194 genotyped and imputed SNPs that passed all QC criteria in 3,712 Chinese Hans from Beijing and Shanghai, of which 1,839 were case subjects, and 1,873 were control subjects. No significant population stratification was observed between case and control subjects using principle component analysis (Supplementary Fig. 2), and the genomic control factor was also quite close to 1.0 (λ = 1.03), suggesting there is no genome-wide inflation due to population stratification for stage 1 samples. The quantile–quantile plot showed substantial deviation from the expected at the lower P values, suggesting that some associations were more significant than expected by chance (Supplementary Fig. 3). SNPs in four previously reported T2D loci (CDKAL1, CDKN2A/B, KCNQ1, and DUSP9) reached genome-wide significance (P < 5 × 10−8) (Fig. 2 and Supplementary Fig. 4), with directional consistency as previously reported (21–25). For the other previously reported T2D loci, apart from three loci that were monomorphic in Chinese Hans, 48 of 51 loci showed directionally consistent association with T2D (binomial test, P = 9.8 × 10−12), of which 19 were associated with T2D at P < 0.05 (Supplementary Table 3). Of these, only the rs7754840 in CDKAL1 showed a significantly larger effect on T2D in Chinese Hans than in white Europeans (P for heterogeneity = 3.33 × 10−4), consistent with our previous findings (26).

Bottom Line: Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians.In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose.Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

Show MeSH
Related in: MedlinePlus