Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

Richa Saxena; Danish Saleheen; Latonya F Been; Martha L Garavito; Timothy Braun; Andrew Bjonnes; Robin Young; Weang Kee Ho; Asif Rasheed; Philippe Frossard; Xueling Sim; Neelam Hassanali; Venkatesan Radha; Manickam Chidambaram; Samuel Liju; Simon D Rees; Daniel Peng-Keat Ng; Tien-Yin Wong; Toshimasa Yamauchi; Kazuo Hara; Yasushi Tanaka; Hiroshi Hirose; Mark I McCarthy; Andrew P Morris; Abdul Basit; Anthony H Barnett; Prasad Katulanda; David Matthews; Viswanathan Mohan; Gurpreet S Wander; Jai Rup Singh; Narinder K Mehra; Sarju Ralhan; M Ilyas Kamboh; John J Mulvihill; Hiroshi Maegawa; Kazuyuki Tobe; Shiro Maeda; Yoon S Cho; E Shyong Tai; M Ann Kelly; John C Chambers; Jaspal S Kooner; Takashi Kadowaki; Panos Deloukas; Daniel J Rader; John Danesh; Dharambir K Sanghera; DIAGRAM Consortium; Marilyn Kelly

doi:10.2337/db12-1077

Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

Richa Saxena, Danish Saleheen, Latonya F Been, Martha L Garavito, Timothy Braun, Andrew Bjonnes, Robin Young, Weang Kee Ho, Asif Rasheed, Philippe Frossard, Xueling Sim, Neelam Hassanali, Venkatesan Radha, Manickam Chidambaram, Samuel Liju, Simon D Rees, Daniel Peng-Keat Ng, Tien-Yin Wong, Toshimasa Yamauchi, Kazuo HaraYasushi Tanaka, Hiroshi Hirose, Mark I McCarthy, Andrew P Morris, Abdul Basit, Anthony H Barnett, Prasad Katulanda, David Matthews, Viswanathan Mohan, Gurpreet S Wander, Jai Rup Singh, Narinder K Mehra, Sarju Ralhan, M Ilyas Kamboh, John J Mulvihill, Hiroshi Maegawa, Kazuyuki Tobe, Shiro Maeda, Yoon S Cho, E Shyong Tai, M Ann Kelly, John C Chambers, Jaspal S Kooner, Takashi Kadowaki, Panos Deloukas, Daniel J Rader, John Danesh, Dharambir K Sanghera, DIAGRAM Consortium, Marilyn Kelly

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Abstract

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 SNPs (P <10(-3)) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 single nucleotide polymorphisms (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.

Original language	English
Journal	Diabetes
DOIs	https://doi.org/10.2337/db12-1077
Publication status	Published - 2013

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Saxena, R., Saleheen, D., Been, L. F., Garavito, M. L., Braun, T., Bjonnes, A., Young, R., Ho, W. K., Rasheed, A., Frossard, P., Sim, X., Hassanali, N., Radha, V., Chidambaram, M., Liju, S., Rees, S. D., Peng-Keat Ng, D., Wong, T-Y., Yamauchi, T., ... Kelly, M. (2013). Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India. Diabetes. https://doi.org/10.2337/db12-1077

@article{6f30a3709c8c48baba2511820ff5aee0,

title = "Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India",

abstract = "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 SNPs (P <10(-3)) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 single nucleotide polymorphisms (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.",

author = "Richa Saxena and Danish Saleheen and Been, {Latonya F} and Garavito, {Martha L} and Timothy Braun and Andrew Bjonnes and Robin Young and Ho, {Weang Kee} and Asif Rasheed and Philippe Frossard and Xueling Sim and Neelam Hassanali and Venkatesan Radha and Manickam Chidambaram and Samuel Liju and Rees, {Simon D} and {Peng-Keat Ng}, Daniel and Tien-Yin Wong and Toshimasa Yamauchi and Kazuo Hara and Yasushi Tanaka and Hiroshi Hirose and McCarthy, {Mark I} and Morris, {Andrew P} and Abdul Basit and Barnett, {Anthony H} and Prasad Katulanda and David Matthews and Viswanathan Mohan and Wander, {Gurpreet S} and Singh, {Jai Rup} and Mehra, {Narinder K} and Sarju Ralhan and Kamboh, {M Ilyas} and Mulvihill, {John J} and Hiroshi Maegawa and Kazuyuki Tobe and Shiro Maeda and Cho, {Yoon S} and Tai, {E Shyong} and Kelly, {M Ann} and Chambers, {John C} and Kooner, {Jaspal S} and Takashi Kadowaki and Panos Deloukas and Rader, {Daniel J} and John Danesh and Sanghera, {Dharambir K} and {DIAGRAM Consortium} and Marilyn Kelly",

year = "2013",

doi = "10.2337/db12-1077",

language = "English",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

}

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, Peng-Keat Ng, D, Wong, T-Y, Yamauchi, T, Hara, K, Tanaka, Y, Hirose, H, McCarthy, MI, Morris, AP, 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, DIAGRAM Consortium & Kelly, M 2013, 'Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India', Diabetes. https://doi.org/10.2337/db12-1077

TY - JOUR

T1 - Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

AU - Saxena, Richa

AU - Saleheen, Danish

AU - Been, Latonya F

AU - Garavito, Martha L

AU - Braun, Timothy

AU - Bjonnes, Andrew

AU - Young, Robin

AU - Ho, Weang Kee

AU - Rasheed, Asif

AU - Frossard, Philippe

AU - Sim, Xueling

AU - Hassanali, Neelam

AU - Radha, Venkatesan

AU - Chidambaram, Manickam

AU - Liju, Samuel

AU - Rees, Simon D

AU - Peng-Keat Ng, Daniel

AU - Wong, Tien-Yin

AU - Yamauchi, Toshimasa

AU - Hara, Kazuo

AU - Tanaka, Yasushi

AU - Hirose, Hiroshi

AU - McCarthy, Mark I

AU - Morris, Andrew P

AU - Basit, Abdul

AU - Barnett, Anthony H

AU - Katulanda, Prasad

AU - Matthews, David

AU - Mohan, Viswanathan

AU - Wander, Gurpreet S

AU - Singh, Jai Rup

AU - Mehra, Narinder K

AU - Ralhan, Sarju

AU - Kamboh, M Ilyas

AU - Mulvihill, John J

AU - Maegawa, Hiroshi

AU - Tobe, Kazuyuki

AU - Maeda, Shiro

AU - Cho, Yoon S

AU - Tai, E Shyong

AU - Kelly, M Ann

AU - Chambers, John C

AU - Kooner, Jaspal S

AU - Kadowaki, Takashi

AU - Deloukas, Panos

AU - Rader, Daniel J

AU - Danesh, John

AU - Sanghera, Dharambir K

AU - DIAGRAM Consortium

AU - Kelly, Marilyn

PY - 2013

Y1 - 2013

N2 - 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 SNPs (P <10(-3)) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 single nucleotide polymorphisms (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.

AB - 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 SNPs (P <10(-3)) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 single nucleotide polymorphisms (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.

U2 - 10.2337/db12-1077

DO - 10.2337/db12-1077

M3 - Article

C2 - 23300278

SN - 0012-1797

JO - Diabetes

JF - Diabetes

ER -

Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India

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