Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India.
Saxena R., Saleheen D., Been LF., Garavito ML., Braun T., Bjonnes A., Young R., Ho WK., Rasheed A., Frossard P., Sim X., Hassanali N., Radha V., Chidambaram M., Liju S., Rees SD., Ng DP-K., Wong T-Y., Yamauchi T., Hara K., Tanaka Y., Hirose H., McCarthy MI., Morris AP., DIAGRAM None., MuTHER None., AGEN None., Basit A., Barnett AH., Katulanda P., Matthews D., Mohan V., Wander GS., Singh JR., Mehra NK., Ralhan S., Kamboh MI., Mulvihill JJ., Maegawa H., Tobe K., Maeda S., Cho YS., Tai ES., Kelly MA., Chambers JC., Kooner JS., Kadowaki T., Deloukas P., Rader DJ., Danesh J., Sanghera DK.
We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻⁴) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10⁻⁸) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⁻³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10⁻⁴) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10⁻⁵ to < 10⁻⁷), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.