Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

MCY Ng; D Shriner; BH Chen; J Li; WM Chen; XQ Guo; JK Liu; SJ Bielinski; LR Yanek; MA Nalls; ME Comeau; LJ Rasmussen-Torvik; RA Jensen; DS Evans; YV Sun; P An; SR Patel; YC Lu; JR Long; LL Armstrong; L Wagenknecht; LY Yang; BM Snively; ND Palmer; P Mudgal; CD Langefeld; KL Keene; BI Freedman; JC Mychaleckyj; U Nayak; LJ Raffel; MO Goodarzi; YDI Chen; HA Taylor; A Correa; M Sims; D Couper; JS Pankow; E Boerwinkle; A Adeyemo; A Doumatey; GJ Chen; RA Mathias; D Vaidya; AB Singleton; AB Zonderman; RP Igo; JR Sedor; EK Kabagambe; DS Siscovick; B McKnight; K Rice; YM Liu; WC Hsueh; W Zhao; LF Bielak; A Kraja; MA Province; EP Bottinger; O Gottesman; QY Cai; W Zheng; WJ Blot; WL Lowe; JA Pacheco; DC Crawford; E Grundberg; SS Rich; MG Hayes; XO Shu; RJF Loos; IB Borecki; PA Peyser; SR Cummings; BM Psaty; M Fornage; SK Iyengar; MK Evans; DM Becker; WHL Kao; JG Wilson; JI Rotter; MM Sale; SM (Simin) Liu; CN Rotimi; DW Bowden

doi:10.1371/journal.pgen.1004517

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

MCY Ng, D Shriner, BH Chen, J Li, WM Chen, XQ Guo, JK Liu, SJ Bielinski, LR Yanek, MA Nalls, ME Comeau, LJ Rasmussen-Torvik, RA Jensen, DS Evans, YV Sun, P An, SR Patel, YC Lu, JR Long, LL ArmstrongL Wagenknecht, LY Yang, BM Snively, ND Palmer, P Mudgal, CD Langefeld, KL Keene, BI Freedman, JC Mychaleckyj, U Nayak, LJ Raffel, MO Goodarzi, YDI Chen, HA Taylor, A Correa, M Sims, D Couper, JS Pankow, E Boerwinkle, A Adeyemo, A Doumatey, GJ Chen, RA Mathias, D Vaidya, AB Singleton, AB Zonderman, RP Igo, JR Sedor, EK Kabagambe, DS Siscovick, B McKnight, K Rice, YM Liu, WC Hsueh, W Zhao, LF Bielak, A Kraja, MA Province, EP Bottinger, O Gottesman, QY Cai, W Zheng, WJ Blot, WL Lowe, JA Pacheco, DC Crawford, E Grundberg, SS Rich, MG Hayes, XO Shu, RJF Loos, IB Borecki, PA Peyser, SR Cummings, BM Psaty, M Fornage, SK Iyengar, MK Evans, DM Becker, WHL Kao, JG Wilson, JI Rotter, MM Sale, SM (Simin) Liu, CN Rotimi, DW Bowden

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Abstract

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15x10(-94) < P < 5x10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2x10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

Original language	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	10
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1004517
Publication status	Published - 2014

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10.1371/journal.pgen.1004517

Cite this

Ng, MCY., Shriner, D., Chen, BH., Li, J., Chen, WM., Guo, XQ., Liu, JK., Bielinski, SJ., Yanek, LR., Nalls, MA., Comeau, ME., Rasmussen-Torvik, LJ., Jensen, RA., Evans, DS., Sun, YV., An, P., Patel, SR., Lu, YC., Long, JR., ... Bowden, DW. (2014). Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes. PLoS Genetics (print), 10(8). https://doi.org/10.1371/journal.pgen.1004517

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title = "Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes",

abstract = "Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15x10(-94) < P < 5x10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2x10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.",

author = "MCY Ng and D Shriner and BH Chen and J Li and WM Chen and XQ Guo and JK Liu and SJ Bielinski and LR Yanek and MA Nalls and ME Comeau and LJ Rasmussen-Torvik and RA Jensen and DS Evans and YV Sun and P An and SR Patel and YC Lu and JR Long and LL Armstrong and L Wagenknecht and LY Yang and BM Snively and ND Palmer and P Mudgal and CD Langefeld and KL Keene and BI Freedman and JC Mychaleckyj and U Nayak and LJ Raffel and MO Goodarzi and YDI Chen and HA Taylor and A Correa and M Sims and D Couper and JS Pankow and E Boerwinkle and A Adeyemo and A Doumatey and GJ Chen and RA Mathias and D Vaidya and AB Singleton and AB Zonderman and RP Igo and JR Sedor and EK Kabagambe and DS Siscovick and B McKnight and K Rice and YM Liu and WC Hsueh and W Zhao and LF Bielak and A Kraja and MA Province and EP Bottinger and O Gottesman and QY Cai and W Zheng and WJ Blot and WL Lowe and JA Pacheco and DC Crawford and E Grundberg and SS Rich and MG Hayes and XO Shu and RJF Loos and IB Borecki and PA Peyser and SR Cummings and BM Psaty and M Fornage and SK Iyengar and MK Evans and DM Becker and WHL Kao and JG Wilson and JI Rotter and MM Sale and Liu, {SM (Simin)} and CN Rotimi and DW Bowden",

year = "2014",

doi = "10.1371/journal.pgen.1004517",

language = "Undefined/Unknown",

volume = "10",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "8",

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Ng, MCY, Shriner, D, Chen, BH, Li, J, Chen, WM, Guo, XQ, Liu, JK, Bielinski, SJ, Yanek, LR, Nalls, MA, Comeau, ME, Rasmussen-Torvik, LJ, Jensen, RA, Evans, DS, Sun, YV, An, P, Patel, SR, Lu, YC, Long, JR, Armstrong, LL, Wagenknecht, L, Yang, LY, Snively, BM, Palmer, ND, Mudgal, P, Langefeld, CD, Keene, KL, Freedman, BI, Mychaleckyj, JC, Nayak, U, Raffel, LJ, Goodarzi, MO, Chen, YDI, Taylor, HA, Correa, A, Sims, M, Couper, D, Pankow, JS, Boerwinkle, E, Adeyemo, A, Doumatey, A, Chen, GJ, Mathias, RA, Vaidya, D, Singleton, AB, Zonderman, AB, Igo, RP, Sedor, JR, Kabagambe, EK, Siscovick, DS, McKnight, B, Rice, K, Liu, YM, Hsueh, WC, Zhao, W, Bielak, LF, Kraja, A, Province, MA, Bottinger, EP, Gottesman, O, Cai, QY, Zheng, W, Blot, WJ, Lowe, WL, Pacheco, JA, Crawford, DC, Grundberg, E, Rich, SS, Hayes, MG, Shu, XO, Loos, RJF, Borecki, IB, Peyser, PA, Cummings, SR, Psaty, BM, Fornage, M, Iyengar, SK, Evans, MK, Becker, DM, Kao, WHL, Wilson, JG, Rotter, JI, Sale, MM, Liu, SM, Rotimi, CN & Bowden, DW 2014, 'Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes', PLoS Genetics (print), vol. 10, no. 8. https://doi.org/10.1371/journal.pgen.1004517

TY - JOUR

T1 - Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

AU - Ng, MCY

AU - Shriner, D

AU - Chen, BH

AU - Li, J

AU - Chen, WM

AU - Guo, XQ

AU - Liu, JK

AU - Bielinski, SJ

AU - Yanek, LR

AU - Nalls, MA

AU - Comeau, ME

AU - Rasmussen-Torvik, LJ

AU - Jensen, RA

AU - Evans, DS

AU - Sun, YV

AU - An, P

AU - Patel, SR

AU - Lu, YC

AU - Long, JR

AU - Armstrong, LL

AU - Wagenknecht, L

AU - Yang, LY

AU - Snively, BM

AU - Palmer, ND

AU - Mudgal, P

AU - Langefeld, CD

AU - Keene, KL

AU - Freedman, BI

AU - Mychaleckyj, JC

AU - Nayak, U

AU - Raffel, LJ

AU - Goodarzi, MO

AU - Chen, YDI

AU - Taylor, HA

AU - Correa, A

AU - Sims, M

AU - Couper, D

AU - Pankow, JS

AU - Boerwinkle, E

AU - Adeyemo, A

AU - Doumatey, A

AU - Chen, GJ

AU - Mathias, RA

AU - Vaidya, D

AU - Singleton, AB

AU - Zonderman, AB

AU - Igo, RP

AU - Sedor, JR

AU - Kabagambe, EK

AU - Siscovick, DS

AU - McKnight, B

AU - Rice, K

AU - Liu, YM

AU - Hsueh, WC

AU - Zhao, W

AU - Bielak, LF

AU - Kraja, A

AU - Province, MA

AU - Bottinger, EP

AU - Gottesman, O

AU - Cai, QY

AU - Zheng, W

AU - Blot, WJ

AU - Lowe, WL

AU - Pacheco, JA

AU - Crawford, DC

AU - Grundberg, E

AU - Rich, SS

AU - Hayes, MG

AU - Shu, XO

AU - Loos, RJF

AU - Borecki, IB

AU - Peyser, PA

AU - Cummings, SR

AU - Psaty, BM

AU - Fornage, M

AU - Iyengar, SK

AU - Evans, MK

AU - Becker, DM

AU - Kao, WHL

AU - Wilson, JG

AU - Rotter, JI

AU - Sale, MM

AU - Liu, SM (Simin)

AU - Rotimi, CN

AU - Bowden, DW

PY - 2014

Y1 - 2014

N2 - Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15x10(-94) < P < 5x10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2x10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

AB - Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15x10(-94) < P < 5x10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2x10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

U2 - 10.1371/journal.pgen.1004517

DO - 10.1371/journal.pgen.1004517

M3 - Article

SN - 1553-7390

VL - 10

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 8

ER -