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Variants Associated with Common Disease Are Not Unusually Differentiated in Frequency across Populations

2005; Elsevier BV; Volume: 78; Issue: 1 Linguagem: Inglês

10.1086/499287

1537-6605

Kirk E. Lohmueller, Matthew M. Mauney, David Reich, John M. Braverman,

Genomics and Rare Diseases

Genetic variants that contribute to risk of common disease may differ in frequency across populations more than random variants in the genome do, perhaps because they have been exposed to population-specific natural selection. To assess this hypothesis empirically, we analyzed data from two groups of single-nucleotide polymorphisms (SNPs) that have shown reproducible (n=9) or reported (n=39) associations with common diseases. We compared the frequency differentiation (between Europeans and Africans) of the disease-associated SNPs with that of random SNPs in the genome. These common-disease–associated SNPs are not significantly more differentiated across populations than random SNPs. Thus, for the data examined here, ethnicity will not be a good predictor of genotype at many common-disease–associated SNPs, just as it is rarely a good predictor of genotype at random SNPs in the genome. Genetic variants that contribute to risk of common disease may differ in frequency across populations more than random variants in the genome do, perhaps because they have been exposed to population-specific natural selection. To assess this hypothesis empirically, we analyzed data from two groups of single-nucleotide polymorphisms (SNPs) that have shown reproducible (n=9) or reported (n=39) associations with common diseases. We compared the frequency differentiation (between Europeans and Africans) of the disease-associated SNPs with that of random SNPs in the genome. These common-disease–associated SNPs are not significantly more differentiated across populations than random SNPs. Thus, for the data examined here, ethnicity will not be a good predictor of genotype at many common-disease–associated SNPs, just as it is rarely a good predictor of genotype at random SNPs in the genome. An open question in medical and population genetics is how much information a person's self-identified ancestry (ethnicity) conveys about his or her risk of common disease (Risch et al. Risch et al., 2002Risch N Burchard E Ziv E Tang H Categorization of humans in biomedical research: genes, race, and disease.Genome Biol. 2002; 3: 2007.1-2007.12Crossref Google Scholar; Burchard et al. Burchard et al., 2003Burchard EG Ziv E Coyle N Gomez SL Tang H Karter AJ Mountain JL Perez-Stable EJ Sheppard D Risch N The importance of race and ethnic background in biomedical research and clinical practice.N Engl J Med. 2003; 348: 1170-1175Crossref PubMed Scopus (777) Google Scholar; Cooper et al. Cooper et al., 2003Cooper RS Kaufman JS Ward R Race and genomics.N Engl J Med. 2003; 348: 1166-1170Crossref PubMed Scopus (477) Google Scholar). 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We set out to test the hypothesis that common-disease–associated SNPs are more differentiated than random SNPs by conducting an empirical evaluation of population differentiation in 48 SNPs associated with common disease. We wanted to study SNPs that were associated with common, complex traits, so we explicitly excluded variants associated with Mendelian diseases. The SNPs were all identified in a way that would not create a bias toward unusually high or low levels of frequency differentiation across populations, since each of them was initially identified in studies of single populations. We first studied nine SNPs reproducibly associated with common disease (table 1). These SNPs satisfied two criteria: (1) >75% of replication studies showed a statistically significant association (Hirschhorn et al. 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For allele frequencies obtained from a meta-analysis, only the reference claiming reproducible association is given.d Allele frequency obtained from the literature involving a European population. Either the general population frequency or the frequency in control groups in an association study was used. To reduce bias, when a control frequency was used for Europeans, a control frequency was also used for Africans. The total number of chromosomes surveyed is given in parentheses after each frequency.e Allele frequency obtained from the literature involving a West African population. The total number of chromosomes surveyed is given in parentheses after each frequency.f δ = The difference in the allele frequency between Europeans and Africans. Open table in a new tab Second, we studied 39 SNPs that have been reported to be associated with common disease (table 2) but for which association has not necessarily been replicated. These were identified by checking the genes sequenced by the Seattle SNPs project (Seattle SNPs Web site) for overlap with the SNPs reported to be associated with common disease in the OMIM and PubMed databases or in table 1 of Hirschhorn et al. (Hirschhorn et al., 2002Hirschhorn JN Lohmueller K Byrne E Hirschhorn K A comprehensive review of genetic association studies.Genet Med. 2002; 4: 45-61Crossref PubMed Scopus (1363) Google Scholar).Table 2Allele-Frequency Data for 39 Reported AssociationsFrequencyGeneDisease/PhenotypeaAD = Alzheimer disease; AIDS = acquired immunodeficiency syndrome; ARDS = acute respiratory distress syndrome; CAD = coronary artery disease; Hp = Helicobacter pylori; MI = myocardial infarction; MS = multiple sclerosis; RA = rheumatoid arthritis; RSV = respiratory syncytial virus; SCD = sickle cell disease.SNPAssociated AllelebThe associated allele is the SNP associated with disease, regardless of whether it is the derived or the ancestral allele. 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