Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study

Christopher S. Carlson, Tara C. Matise, Kari E. North, Christopher A. Haiman, Megan D. Fesinmeyer, Steven Buyske, Fredrick R. Schumacher, Ulrike Peters, Nora Franceschini, Marylyn Deriggi Ritchie, David J. Duggan, Kylee L. Spencer, Logan Dumitrescu, Charles B. Eaton, Fridtjof Thomas, Alicia Young, Cara Carty, Gerardo Heiss, Loic Le Marchand, Dana C. CrawfordLucia A. Hindorff, Charles L. Kooperberg

Research output: Contribution to journalArticle

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Abstract

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

Original languageEnglish (US)
Article numbere1001661
JournalPLoS biology
Volume11
Issue number9
DOIs
StatePublished - Jan 1 2013

Fingerprint

Epidemiology
Genome-Wide Association Study
Genomics
Dilution
epidemiology
ancestry
Genes
genomics
Population
Medical problems
genome-wide association study
Refining
Genetic Models
Population Genetics
Population Density
African Americans
Lipids
Type 2 Diabetes Mellitus
refining
Body Mass Index

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Carlson, C. S., Matise, T. C., North, K. E., Haiman, C. A., Fesinmeyer, M. D., Buyske, S., ... Kooperberg, C. L. (2013). Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study. PLoS biology, 11(9), [e1001661]. https://doi.org/10.1371/journal.pbio.1001661
Carlson, Christopher S. ; Matise, Tara C. ; North, Kari E. ; Haiman, Christopher A. ; Fesinmeyer, Megan D. ; Buyske, Steven ; Schumacher, Fredrick R. ; Peters, Ulrike ; Franceschini, Nora ; Ritchie, Marylyn Deriggi ; Duggan, David J. ; Spencer, Kylee L. ; Dumitrescu, Logan ; Eaton, Charles B. ; Thomas, Fridtjof ; Young, Alicia ; Carty, Cara ; Heiss, Gerardo ; Le Marchand, Loic ; Crawford, Dana C. ; Hindorff, Lucia A. ; Kooperberg, Charles L. / Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry : The PAGE Study. In: PLoS biology. 2013 ; Vol. 11, No. 9.
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abstract = "The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25{\%} of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.",
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Carlson, CS, Matise, TC, North, KE, Haiman, CA, Fesinmeyer, MD, Buyske, S, Schumacher, FR, Peters, U, Franceschini, N, Ritchie, MD, Duggan, DJ, Spencer, KL, Dumitrescu, L, Eaton, CB, Thomas, F, Young, A, Carty, C, Heiss, G, Le Marchand, L, Crawford, DC, Hindorff, LA & Kooperberg, CL 2013, 'Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study', PLoS biology, vol. 11, no. 9, e1001661. https://doi.org/10.1371/journal.pbio.1001661

Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry : The PAGE Study. / Carlson, Christopher S.; Matise, Tara C.; North, Kari E.; Haiman, Christopher A.; Fesinmeyer, Megan D.; Buyske, Steven; Schumacher, Fredrick R.; Peters, Ulrike; Franceschini, Nora; Ritchie, Marylyn Deriggi; Duggan, David J.; Spencer, Kylee L.; Dumitrescu, Logan; Eaton, Charles B.; Thomas, Fridtjof; Young, Alicia; Carty, Cara; Heiss, Gerardo; Le Marchand, Loic; Crawford, Dana C.; Hindorff, Lucia A.; Kooperberg, Charles L.

In: PLoS biology, Vol. 11, No. 9, e1001661, 01.01.2013.

Research output: Contribution to journalArticle

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T1 - Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry

T2 - The PAGE Study

AU - Carlson, Christopher S.

AU - Matise, Tara C.

AU - North, Kari E.

AU - Haiman, Christopher A.

AU - Fesinmeyer, Megan D.

AU - Buyske, Steven

AU - Schumacher, Fredrick R.

AU - Peters, Ulrike

AU - Franceschini, Nora

AU - Ritchie, Marylyn Deriggi

AU - Duggan, David J.

AU - Spencer, Kylee L.

AU - Dumitrescu, Logan

AU - Eaton, Charles B.

AU - Thomas, Fridtjof

AU - Young, Alicia

AU - Carty, Cara

AU - Heiss, Gerardo

AU - Le Marchand, Loic

AU - Crawford, Dana C.

AU - Hindorff, Lucia A.

AU - Kooperberg, Charles L.

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Y1 - 2013/1/1

N2 - The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

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