A genome-wide association search for type 2 diabetes genes in African Americans

Nicholette D Palmer; Caitrin W McDonough; Pamela J Hicks; Bong H Roh; Maria R Wing; S Sandy An; Jessica M Hester; Jessica N Cooke; Meredith A Bostrom; Megan E Rudock; Matthew E Talbert; Joshua P Lewis; Assiamira Ferrara; Lingyi Lu; Julie T Ziegler; Michele M Sale; Jasmin Divers; Daniel Shriner; Adebowale Adeyemo; Charles N Rotimi; Maggie C Y Ng; Carl D Langefeld; Barry I Freedman; Donald W Bowden; Benjamin F Voight; Laura J Scott; Valgerdur Steinthorsdottir; Andrew P Morris; Christian Dina; Ryan P Welch; Eleftheria Zeggini; Cornelia Huth; Yurii S Aulchenko; Gudmar Thorleifsson; Laura J McCulloch; Teresa Ferreira; Harald Grallert; Najaf Amin; Guanming Wu; Cristen J Willer; Soumya Raychaudhuri; Steve A McCarroll; Claudia Langenberg; Niels Grarup; Torben Jørgensen; Thomas Sparsø; Torben Hansen; Oluf Pedersen; Peter Schwarz; Fredrik Karpe; DIAGRAM Consortium

doi:10.1371/journal.pone.0029202

A genome-wide association search for type 2 diabetes genes in African Americans

Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N RotimiMaggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Niels Grarup, Torben Jørgensen, Thomas Sparsø, Torben Hansen, Oluf Pedersen, Peter Schwarz, Fredrik Karpe, DIAGRAM Consortium

130 Citationer (Scopus)

Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10^-8). SNP rs7560163 (P = 7.0×10^-9, OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10^-5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Originalsprog	Engelsk
Tidsskrift	P L o S One
Vol/bind	7
Udgave nummer	1
Sider (fra-til)	e29202
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0029202
Status	Udgivet - 4 jan. 2012

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Palmer, N. D., McDonough, C. W., Hicks, P. J., Roh, B. H., Wing, M. R., An, S. S., Hester, J. M., Cooke, J. N., Bostrom, M. A., Rudock, M. E., Talbert, M. E., Lewis, J. P., Ferrara, A., Lu, L., Ziegler, J. T., Sale, M. M., Divers, J., Shriner, D., Adeyemo, A., ... DIAGRAM Consortium (2012). A genome-wide association search for type 2 diabetes genes in African Americans. P L o S One, 7(1), e29202. https://doi.org/10.1371/journal.pone.0029202

Palmer, ND, McDonough, CW, Hicks, PJ, Roh, BH, Wing, MR, An, SS, Hester, JM, Cooke, JN, Bostrom, MA, Rudock, ME, Talbert, ME, Lewis, JP, Ferrara, A, Lu, L, Ziegler, JT, Sale, MM, Divers, J, Shriner, D, Adeyemo, A, Rotimi, CN, Ng, MCY, Langefeld, CD, Freedman, BI, Bowden, DW, Voight, BF, Scott, LJ, Steinthorsdottir, V, Morris, AP, Dina, C, Welch, RP, Zeggini, E, Huth, C, Aulchenko, YS, Thorleifsson, G, McCulloch, LJ, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, CJ, Raychaudhuri, S, McCarroll, SA, Langenberg, C, Grarup, N, Jørgensen, T, Sparsø, T, Hansen, T , Pedersen, O , Schwarz, P, Karpe, F & DIAGRAM Consortium 2012, 'A genome-wide association search for type 2 diabetes genes in African Americans', P L o S One, bind 7, nr. 1, s. e29202. https://doi.org/10.1371/journal.pone.0029202

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title = "A genome-wide association search for type 2 diabetes genes in African Americans",

abstract = "African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10-8). SNP rs7560163 (P = 7.0×10-9, OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10-5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.",

keywords = "Adult, African Americans, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic",

author = "Palmer, {Nicholette D} and McDonough, {Caitrin W} and Hicks, {Pamela J} and Roh, {Bong H} and Wing, {Maria R} and An, {S Sandy} and Hester, {Jessica M} and Cooke, {Jessica N} and Bostrom, {Meredith A} and Rudock, {Megan E} and Talbert, {Matthew E} and Lewis, {Joshua P} and Assiamira Ferrara and Lingyi Lu and Ziegler, {Julie T} and Sale, {Michele M} and Jasmin Divers and Daniel Shriner and Adebowale Adeyemo and Rotimi, {Charles N} and Ng, {Maggie C Y} and Langefeld, {Carl D} and Freedman, {Barry I} and Bowden, {Donald W} and Voight, {Benjamin F} and Scott, {Laura J} and Valgerdur Steinthorsdottir and Morris, {Andrew P} and Christian Dina and Welch, {Ryan P} and Eleftheria Zeggini and Cornelia Huth and Aulchenko, {Yurii S} and Gudmar Thorleifsson and McCulloch, {Laura J} and Teresa Ferreira and Harald Grallert and Najaf Amin and Guanming Wu and Willer, {Cristen J} and Soumya Raychaudhuri and McCarroll, {Steve A} and Claudia Langenberg and Niels Grarup and Torben J{\o}rgensen and Thomas Spars{\o} and Torben Hansen and Oluf Pedersen and Peter Schwarz and Fredrik Karpe and {DIAGRAM Consortium}",

year = "2012",

month = jan,

day = "4",

doi = "10.1371/journal.pone.0029202",

language = "English",

volume = "7",

pages = "e29202",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "1",

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TY - JOUR

T1 - A genome-wide association search for type 2 diabetes genes in African Americans

AU - Palmer, Nicholette D

AU - McDonough, Caitrin W

AU - Hicks, Pamela J

AU - Roh, Bong H

AU - Wing, Maria R

AU - An, S Sandy

AU - Hester, Jessica M

AU - Cooke, Jessica N

AU - Bostrom, Meredith A

AU - Rudock, Megan E

AU - Talbert, Matthew E

AU - Lewis, Joshua P

AU - Ferrara, Assiamira

AU - Lu, Lingyi

AU - Ziegler, Julie T

AU - Sale, Michele M

AU - Divers, Jasmin

AU - Shriner, Daniel

AU - Adeyemo, Adebowale

AU - Rotimi, Charles N

AU - Ng, Maggie C Y

AU - Langefeld, Carl D

AU - Freedman, Barry I

AU - Bowden, Donald W

AU - Voight, Benjamin F

AU - Scott, Laura J

AU - Steinthorsdottir, Valgerdur

AU - Morris, Andrew P

AU - Dina, Christian

AU - Welch, Ryan P

AU - Zeggini, Eleftheria

AU - Huth, Cornelia

AU - Aulchenko, Yurii S

AU - Thorleifsson, Gudmar

AU - McCulloch, Laura J

AU - Ferreira, Teresa

AU - Grallert, Harald

AU - Amin, Najaf

AU - Wu, Guanming

AU - Willer, Cristen J

AU - Raychaudhuri, Soumya

AU - McCarroll, Steve A

AU - Langenberg, Claudia

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Sparsø, Thomas

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Schwarz, Peter

AU - Karpe, Fredrik

AU - DIAGRAM Consortium

PY - 2012/1/4

Y1 - 2012/1/4

N2 - African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10-8). SNP rs7560163 (P = 7.0×10-9, OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10-5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

AB - African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10-8). SNP rs7560163 (P = 7.0×10-9, OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10-5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

KW - Adult

KW - African Americans

KW - Aged

KW - Case-Control Studies

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Male

KW - Meta-Analysis as Topic

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Validation Studies as Topic

U2 - 10.1371/journal.pone.0029202

DO - 10.1371/journal.pone.0029202

M3 - Journal article

C2 - 22238593

SN - 1932-6203

VL - 7

SP - e29202

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 1

ER -

A genome-wide association search for type 2 diabetes genes in African Americans

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