Association Mapping in Structured Populations

Pritchard, Jonathan K.; Stephens, Matthew; Rosenberg, Noah A.; Donnelly, Peter

doi:10.1086/302959

Cited by 1,759 publications

(1,554 citation statements)

References 15 publications

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“…22,23 We have previously observed a strong correlation between self-reported race and individual admixture in this study sample. 21 We obtained similar results under both models during our analyses using individual estimates of admixture and using selfreported race.…”

Section: Evaluation Of Population Structuresupporting

confidence: 52%

Associations between the human MHC and sustained virologic response in the treatment of chronic hepatitis C virus infection

Rhodes

Erlich

et al. 2008

Genes Immun

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The human major histocompatability complex (MHC) genes encode the human leukocyte antigens, which are important in antigen presentation and regulation of CD8 þ and CD4 þ T cells. Response to therapies in hepatitis C virus (HCV) infection is highly variable (30-80%) and lower response rates have been reported among African Americans (AA; B30%) compared to Caucasian Americans (CA; B50%) infected with genotype-1 viruses. We evaluated whether MHC gene variants were associated with response to therapy and racial differences in AA and CA sustained virologic response (SVR) rates. We genotyped alleles at 8 MHC loci: 3 class I (A, B and C) and 5 class II (DRB1, DQA1, DQB1, DPA1 and DPB1) loci in 373 individuals (179 AA and 194 CA) with genotype-1 HCV infections, who were treated with peginterferon-a-2a and ribavirin. We observed carriage of A*02 (RR ¼ 1.33(1.08-1.64); P ¼ 0.008), B *58 (RR ¼ 1.84(1.24-2.73); P ¼ 0.002) and DPB1*1701 (RR ¼ 1.57(1.09-2.26); P ¼ 0.015) to be associated with SVR after adjustment for other predictors of response. In analysis of AA and CA subgroups separately, we observed potential, though not statistically significant, differences in these MHC associations. Variation in the immunogenetic background of HCV-infected individuals might account for some observed variation in viral-specific immunity and courses of disease. In this regard, future studies examining broader patient populations are warranted.

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Section: Evaluation Of Population Structuresupporting

confidence: 52%

Associations between the human MHC and sustained virologic response in the treatment of chronic hepatitis C virus infection

Rhodes

Erlich

et al. 2008

Genes Immun

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“…Several statistical methods have recently been developed to account for population structure so that association studies can proceed even when structure is present 16,[19][20][21][22][23][24][25] . One commonly used method, Genomic Control, uses a set of anonymous markers to correct for population stratification 16 .…”

Section: Figurementioning

confidence: 99%

The effects of human population structure on large genetic association studies

et al. 2004

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Large-scale association studies hold substantial promise for unraveling the genetic basis of common human diseases. A wellknown problem with such studies is the presence of undetected population structure, which can lead to both false positive results and failures to detect genuine associations. Here we examine ∼15,000 genome-wide single-nucleotide polymorphisms typed in three population groups to assess the consequences of population structure on the coming generation of association studies. The consequences of population structure on association outcomes increase markedly with sample size. For the size of study needed to detect typical genetic effects in common diseases, even the modest levels of population structure within population groups cannot safely be ignored. We also examine one method for correcting for population structure (Genomic Control). Although it often performs well, it may not correct for structure if too few loci are used and may overcorrect in other settings, leading to substantial loss of power. The results of our analysis can guide the design of large-scale association studies.Recent advances in genotyping technologies and increases in genetic marker availability have paved the way for association studies on genomic scales 1 . A potential problem for every population-based association study is the presence of undetected population structure that can mimic the signal of association and lead to more false positives or to missed real effects (Fig. 1). These concerns have influenced the design, interpretation and funding of association studies during the past decade 2 . Still, levels of population structure in many ethnic groups are typically small, and despite concerns 3,4 , there is an increasing sense 5,6 that the problem is not serious if association studies avoid gross levels of population structure.Upcoming association studies will genotype many markers and evaluate many individuals, owing to the realization that case-control studies powered to detect realistic effect sizes will typically require thousands of individuals 7,8 . This concern raises two general questions: (i) how much underlying structure is there in various human populations and when might this pose problems for large-scale association studies, and (ii) how accurate and efficient are available methods for correcting for population structure in case-control studies?Using genome-wide single-nucleotide polymorphisms (SNPs) in multiple populations (European Americans, African Americans and Asians of known Japanese or Chinese ancestry), we quantified the extent of population structure within and between the populations and then examined the consequences of population structure for association studies. Figure 1 The effects of population structure at a SNP locus. If the study population consists of subpopulations that differ genetically, and if disease prevalence also differs across these subpopulations, then the proportions of cases and controls sampled from each subpopulation will tend to differ, as will allele or genotype fre...

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“…Subjects' ancestries were estimated using a set of unlinked genetic markers by Bayesian cluster analysis, using the procedures and software developed by Pritchard and colleagues (http://pritch.bsd.uchicago.edu/software.html) (Falush et al, 2003;Pritchard et al, 2000;Pritchard and Rosenberg, 1999). Pritchard's software program STRUC-TURE implements Bayesian cluster modeling that can recognize cryptic population genetic patterns without prior information of population origins.…”

Section: Ancestral Proportion Scoresmentioning

confidence: 99%

Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders

Stein

Schork

Gelernter

2007

Neuropsychopharmacol

204

146

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Anxiety sensitivity (AS) is a dispositional characteristic that predisposes to the development of anxiety disorders (eg, panic and posttraumatic stress disorder) and major depression. AS is subject to genetic and environmental influences, the former as yet unidentified and the latter known to include childhood maltreatment. The serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) has been associated with depression, but most consistently in the context of environmental stress. We tested the hypothesis that 5-HTTLPR genotype and childhood maltreatment would interact to increase susceptibility to AS in young adults. Subjects were European-American college undergraduates (N ¼ 150, median age 18 years) characterized on a measures of AS (Anxiety Sensitivity Index) and retrospective childhood maltreatment (Childhood Trauma Questionnaire [CTQ]). 5-HTTLPR genotypes were obtained from blood-derived DNA. Linear regression was used to model relationships between 5-HTTLPR, childhood emotional abuse, and AS; covariates such as sex, neuroticism, and ancestral proportion scores were incorporated into some models in a larger, ethnically heterogenous sample (N ¼ 247) to evaluate robustness of the findings to model assumptions. A statistically signficant interaction was observed between levels of childhood emotional (or physical) maltreatment and 5-HTTLPR genotype. Specifically, S/S individuals with higher levels of maltreatment had significantly higher levels of AS than subjects in other groups. No such relationship was found for neuroticism, attesting to the possible specificity of the findings for AS. Findings were consistently robust to the inclusion of covariates, and were not confounded by population stratification. In conclusion, these results provide evidence of a specific genetic influence on anxiety sensitivityFan intermediate phenotype for anxiety (and depressive) disorders; this effect is modified by severity of childhood maltreatment. These findings are consistent with the notion that 5-HTTLPR operates broadly to moderate emotional responsivity to stress.

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Association Mapping in Structured Populations

Cited by 1,759 publications

References 15 publications

Associations between the human MHC and sustained virologic response in the treatment of chronic hepatitis C virus infection

Associations between the human MHC and sustained virologic response in the treatment of chronic hepatitis C virus infection

The effects of human population structure on large genetic association studies

Gene-by-Environment (Serotonin Transporter and Childhood Maltreatment) Interaction for Anxiety Sensitivity, an Intermediate Phenotype for Anxiety Disorders

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