Fine mapping and identification of BMI loci in African Americans

Jian Gong, Fredrick Schumacher, Unhee Lim, Lucia A. Hindorff, Jeff Haessler, Steven Buyske, Christopher S. Carlson, Stephanie Rosse, Petra Bůžková, Myriam Fornage, Myron Gross, Nathan Pankratz, James S. Pankow, Pamela J. Schreiner, Richard Cooper, Georg Ehret, C. Charles Gu, Denise Houston, Marguerite R. Irvin, Rebecca Jackson & 26 others Lew Kuller, Brian Henderson, Iona Cheng, Lynne Wilkens, Mark Leppert, Cora E. Lewis, Rongling Li, Khanh Dung H. Nguyen, Robert Goodloe, Eric Farber-Eger, Jonathan Boston, Holli H. Dilks, Marylyn Deriggi Ritchie, Jay Fowke, Loreall Pooler, Misa Graff, Lindsay Fernandez-Rhodes, Barbara Cochrane, Eric Boerwinkle, Charles Kooperberg, Tara C. Matise, Loic Le Marchand, Dana C. Crawford, Christopher A. Haiman, Kari E. North, Ulrike Peters

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Abstract

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10-5. Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r2 > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10-8) and DHX34 (rs4802349, p = 1.2 × 10-7), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

Original languageEnglish (US)
Pages (from-to)661-671
Number of pages11
JournalAmerican Journal of Human Genetics
Volume93
Issue number4
DOIs
StatePublished - Oct 3 2013

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African Americans
Body Mass Index
Genome-Wide Association Study
Population
Single Nucleotide Polymorphism
Brain-Derived Neurotrophic Factor
Linkage Disequilibrium
Genomics
Ethnic Groups
Epidemiology
Genotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Gong, J., Schumacher, F., Lim, U., Hindorff, L. A., Haessler, J., Buyske, S., ... Peters, U. (2013). Fine mapping and identification of BMI loci in African Americans. American Journal of Human Genetics, 93(4), 661-671. https://doi.org/10.1016/j.ajhg.2013.08.012
Gong, Jian ; Schumacher, Fredrick ; Lim, Unhee ; Hindorff, Lucia A. ; Haessler, Jeff ; Buyske, Steven ; Carlson, Christopher S. ; Rosse, Stephanie ; Bůžková, Petra ; Fornage, Myriam ; Gross, Myron ; Pankratz, Nathan ; Pankow, James S. ; Schreiner, Pamela J. ; Cooper, Richard ; Ehret, Georg ; Gu, C. Charles ; Houston, Denise ; Irvin, Marguerite R. ; Jackson, Rebecca ; Kuller, Lew ; Henderson, Brian ; Cheng, Iona ; Wilkens, Lynne ; Leppert, Mark ; Lewis, Cora E. ; Li, Rongling ; Nguyen, Khanh Dung H. ; Goodloe, Robert ; Farber-Eger, Eric ; Boston, Jonathan ; Dilks, Holli H. ; Ritchie, Marylyn Deriggi ; Fowke, Jay ; Pooler, Loreall ; Graff, Misa ; Fernandez-Rhodes, Lindsay ; Cochrane, Barbara ; Boerwinkle, Eric ; Kooperberg, Charles ; Matise, Tara C. ; Le Marchand, Loic ; Crawford, Dana C. ; Haiman, Christopher A. ; North, Kari E. ; Peters, Ulrike. / Fine mapping and identification of BMI loci in African Americans. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 4. pp. 661-671.
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abstract = "Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10-5. Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r2 > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10-8) and DHX34 (rs4802349, p = 1.2 × 10-7), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.",
author = "Jian Gong and Fredrick Schumacher and Unhee Lim and Hindorff, {Lucia A.} and Jeff Haessler and Steven Buyske and Carlson, {Christopher S.} and Stephanie Rosse and Petra Bůžkov{\'a} and Myriam Fornage and Myron Gross and Nathan Pankratz and Pankow, {James S.} and Schreiner, {Pamela J.} and Richard Cooper and Georg Ehret and Gu, {C. Charles} and Denise Houston and Irvin, {Marguerite R.} and Rebecca Jackson and Lew Kuller and Brian Henderson and Iona Cheng and Lynne Wilkens and Mark Leppert and Lewis, {Cora E.} and Rongling Li and Nguyen, {Khanh Dung H.} and Robert Goodloe and Eric Farber-Eger and Jonathan Boston and Dilks, {Holli H.} and Ritchie, {Marylyn Deriggi} and Jay Fowke and Loreall Pooler and Misa Graff and Lindsay Fernandez-Rhodes and Barbara Cochrane and Eric Boerwinkle and Charles Kooperberg and Matise, {Tara C.} and {Le Marchand}, Loic and Crawford, {Dana C.} and Haiman, {Christopher A.} and North, {Kari E.} and Ulrike Peters",
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Gong, J, Schumacher, F, Lim, U, Hindorff, LA, Haessler, J, Buyske, S, Carlson, CS, Rosse, S, Bůžková, P, Fornage, M, Gross, M, Pankratz, N, Pankow, JS, Schreiner, PJ, Cooper, R, Ehret, G, Gu, CC, Houston, D, Irvin, MR, Jackson, R, Kuller, L, Henderson, B, Cheng, I, Wilkens, L, Leppert, M, Lewis, CE, Li, R, Nguyen, KDH, Goodloe, R, Farber-Eger, E, Boston, J, Dilks, HH, Ritchie, MD, Fowke, J, Pooler, L, Graff, M, Fernandez-Rhodes, L, Cochrane, B, Boerwinkle, E, Kooperberg, C, Matise, TC, Le Marchand, L, Crawford, DC, Haiman, CA, North, KE & Peters, U 2013, 'Fine mapping and identification of BMI loci in African Americans', American Journal of Human Genetics, vol. 93, no. 4, pp. 661-671. https://doi.org/10.1016/j.ajhg.2013.08.012

Fine mapping and identification of BMI loci in African Americans. / Gong, Jian; Schumacher, Fredrick; Lim, Unhee; Hindorff, Lucia A.; Haessler, Jeff; Buyske, Steven; Carlson, Christopher S.; Rosse, Stephanie; Bůžková, Petra; Fornage, Myriam; Gross, Myron; Pankratz, Nathan; Pankow, James S.; Schreiner, Pamela J.; Cooper, Richard; Ehret, Georg; Gu, C. Charles; Houston, Denise; Irvin, Marguerite R.; Jackson, Rebecca; Kuller, Lew; Henderson, Brian; Cheng, Iona; Wilkens, Lynne; Leppert, Mark; Lewis, Cora E.; Li, Rongling; Nguyen, Khanh Dung H.; Goodloe, Robert; Farber-Eger, Eric; Boston, Jonathan; Dilks, Holli H.; Ritchie, Marylyn Deriggi; Fowke, Jay; Pooler, Loreall; Graff, Misa; Fernandez-Rhodes, Lindsay; Cochrane, Barbara; Boerwinkle, Eric; Kooperberg, Charles; Matise, Tara C.; Le Marchand, Loic; Crawford, Dana C.; Haiman, Christopher A.; North, Kari E.; Peters, Ulrike.

In: American Journal of Human Genetics, Vol. 93, No. 4, 03.10.2013, p. 661-671.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fine mapping and identification of BMI loci in African Americans

AU - Gong, Jian

AU - Schumacher, Fredrick

AU - Lim, Unhee

AU - Hindorff, Lucia A.

AU - Haessler, Jeff

AU - Buyske, Steven

AU - Carlson, Christopher S.

AU - Rosse, Stephanie

AU - Bůžková, Petra

AU - Fornage, Myriam

AU - Gross, Myron

AU - Pankratz, Nathan

AU - Pankow, James S.

AU - Schreiner, Pamela J.

AU - Cooper, Richard

AU - Ehret, Georg

AU - Gu, C. Charles

AU - Houston, Denise

AU - Irvin, Marguerite R.

AU - Jackson, Rebecca

AU - Kuller, Lew

AU - Henderson, Brian

AU - Cheng, Iona

AU - Wilkens, Lynne

AU - Leppert, Mark

AU - Lewis, Cora E.

AU - Li, Rongling

AU - Nguyen, Khanh Dung H.

AU - Goodloe, Robert

AU - Farber-Eger, Eric

AU - Boston, Jonathan

AU - Dilks, Holli H.

AU - Ritchie, Marylyn Deriggi

AU - Fowke, Jay

AU - Pooler, Loreall

AU - Graff, Misa

AU - Fernandez-Rhodes, Lindsay

AU - Cochrane, Barbara

AU - Boerwinkle, Eric

AU - Kooperberg, Charles

AU - Matise, Tara C.

AU - Le Marchand, Loic

AU - Crawford, Dana C.

AU - Haiman, Christopher A.

AU - North, Kari E.

AU - Peters, Ulrike

PY - 2013/10/3

Y1 - 2013/10/3

N2 - Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10-5. Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r2 > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10-8) and DHX34 (rs4802349, p = 1.2 × 10-7), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

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Gong J, Schumacher F, Lim U, Hindorff LA, Haessler J, Buyske S et al. Fine mapping and identification of BMI loci in African Americans. American Journal of Human Genetics. 2013 Oct 3;93(4):661-671. https://doi.org/10.1016/j.ajhg.2013.08.012