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PubMed2002

[Use of case-parents trio for epidemiological studies of association between genetic polymorphisms and complex diseases].

In case-control studies, spurious associations between allelic variants in candidate genes and disease may arise as a result of population stratification by ethnicity. In epidemiological terms, the ethnic group would act as a confounding factor if both the genotype frequency and the incidence/prevalence of a given chronic disease vary across ethnic groups. Population stratification is a key element in the study of population dynamics and the knowledge of the disparity in health-related conditions among strata has important social and public health implications. However, it would not be scientifically correct to conclude a causal gene-disease association in situations in which the association arises as a consequence of a particular population structure. Although the relevance and magnitude of the bias derived from this confounding, effect would be different depending on the population considered, there has been an increased use of study designs such as the case-parent study, that avoids the effect of population stratification by ethnicity. In this article, we review the analysis of case-parent trios using unrelated affected cases as an epidemiological study design for testing association between genetic polymorphisms and disease.

Alleles↗
PubMed2005

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations.

Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which, cases and controls are matched by admixture, can be an appealing and a suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments. Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is a substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV(1), a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P=0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, beta(2) adrenergic receptor (beta(2)AR) and DeltaFEF(25-75), an asthma-related phenotype, as an example, we demonstrated population stratification was not a confounder in our genetic association. Our present work demonstrates that admixture-matched case-control strategies can efficiently control population stratification confounding in admixed populations.

Adolescent↗
PubMed2006

Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease.

Linkage studies have defined susceptibility regions for late-onset Parkinson disease (PD) on chromosomes 1 and 2, but specific genetic variants have not been definitively identified. Here we report the results of a case-control study to identify disease-associated single nucleotide polymorphisms (SNPs) in these loci. In the initial phase of our study, we genotyped two putative functional SNPs in ubiquitin-specific protease 24 (USP24), a biological candidate gene within the chromosome 1 linkage region, and scanned the chromosome 2 linkage peak with 43 SNPs in a sample set of 224 PD cases and 186 matched controls. Both USP24 SNPs were significantly associated with disease risk (p = 0.0037 for rs1165222:T > C, p.Thr195ILe, and p = 0.037 for rs13312:C > G, a SNP in the 3'-untranslated region), and one marker, rs1048603:C > T, p.Arg1123Cys, in USP40 was significant from the chromosome 2 scan (p = 0.038). Further genotyping of the region surrounding these initial markers led us to identify 19 additional SNPs with strong disease association. In the second phase, we genotyped the 22 significant markers in an additional 110 cases and 162 controls, which together with part of the initial sample set (201 cases and 149 controls) constitute an expanded sample set of 311 age- and gender-matched case-control pairs. Twenty-one markers were significant in the expanded sample set (most significant allelic p-value: 0.0006 for rs287235:C > G on chromosome 1, and 0.005 for rs838552:T > C on chromosome 2), and six SNPs in USP24 remained significant after conservatively adjusting for testing 27 markers (pBonferroni = 0.017-0.049). It is unlikely that population stratification contributed to this finding, as population stratification was undetectable in our sample set using 78 null markers. Our data suggest that genetic variants in USP24 and USP40 affect the risk for late-onset PD, which is consistent with the predicted role of the ubiquitination pathway in PD etiology.

Age of Onset↗
PubMed2006

PSMIX: an R package for population structure inference via maximum likelihood method.

BACKGROUND: Inference of population stratification and individual admixture from genetic markers is an integrative part of a study in diverse situations, such as association mapping and evolutionary studies. Bayesian methods have been proposed for population stratification and admixture inference using multilocus genotypes and widely used in practice. However, these Bayesian methods demand intensive computation resources and may run into convergence problem in Markov Chain Monte Carlo based posterior samplings. RESULTS: We have developed PSMIX, an R package based on maximum likelihood method using expectation-maximization algorithm, for inference of population stratification and individual admixture. CONCLUSION: Compared with software based on Bayesian methods (e.g., STRUCTURE), PSMIX has similar accuracy, but more efficient computations.PSMIX and its supplemental documents are freely available at http://bioinformatics.med.yale.edu/PSMIX.

Algorithms↗
PubMed2001

Combined linkage and association analysis in pedigrees.

We applied a combined linkage and association model for quantitative traits in pedigrees to identify possible functional polymorphisms and to test for association resulting from population stratification and admixture. Functional polymorphisms are identified as variants that are significantly associated with a trait (high chi 2 value) and showing no residual evidence of linkage (low lod score). Applying our model to the simulated data in the population isolate (replicate 1) we correctly identified the polymorphism in gene 6 (MG1) that affects Q1. Without modeling association the lod score for Q1 was 5.4. At the site of the functional variant (5782 bp) the association chi 2 was 88.1 on 1 df (p < 0.001) and the lod score was 0.003. We estimated a 3.7-unit increase in the average Q1 for each extra copy of the polymorphism (95% CI = 2.95-4.41) and there was no evidence of population stratification or admixture (chi 2 = 0.08 on 2 df). For Q5 and gene 2, modeling the sequence variants at 11 loci simultaneously identified multiple functional variants. Including the main effect of 11 marker genotypes reduced the lod score at gene 2 from 8.7 to 0.9. Again, no evidence of population stratification or admixture was found (all chi 2 < 4.9 on 2 df; p > 0.05).

Adult↗
PubMed2005

Host microsatellite alleles in malaria predisposition?

BACKGROUND: Malaria is a serious, sometimes fatal, disease caused by Plasmodium infection of human red blood cells. The host-parasite co-evolutionary processes are well understood by the association of coding variations such as G6PD, Duffy blood group receptor, HLA, and beta-globin gene variants with malaria resistance. The profound genetic diversity in host is attributed to polymorphic microsatellites loci. The microsatellite alleles in bacterial species are known to have aided their survival in fatal environmental conditions. The fascinating question is whether microsatellites are genomic cushion in the human genome to combat disease stress and has cause-effect relationships with infections. PRESENTATION OF THE HYPOTHESIS: It is hypothesized that repeat units or alleles of microsatellites TH01 and D5S818, located in close proximity to beta-globin gene and immune regulatory region in human play a role in malaria predisposition. Association of alleles at aforesaid microsatellites with malaria infection was analysed. To overrule the false association in unrecognized population stratification, structure analysis and AMOVA were performed among the sampled groups. TESTING OF HYPOTHESIS: Associations of microsatellite alleles with malaria infection were verified using recombination rate, Chi-square, and powerful likelihood tests. Further investigation of population genetic structure, and AMOVA was done to rule out the confounding effects of population stratification in interpretation of association studies. IMPLICATION OF THE HYPOTHESIS: Lower recombination rate (theta) between microsatellites and genes implicated in host fitness; positive association between alleles-13 (D5S818), 9 (TH01) and strong susceptibility to Plasmodium falciparum; and alleles-12 (D5S818) and 6 (TH01) rendering resistance to human host were evident. The interesting fact emerging from the study was that while predisposition to malaria was a prehistoric attribute, among TH01 alleles; evolution of resistant allele-6 was a recent phenomenon, which could conceivably be driven by infection related selective forces. The host's microsatellite allelic associations with malaria infection were valid in the light of low genetic variance between sampled groups and no population stratification.

Alleles↗
PubMed2005

Power and related statistical properties of conditional likelihood score tests for association studies in nuclear families with parental genotypes.

Both population based and family based case control studies are used to test whether particular genotypes are associated with disease. While population based studies have more power, cryptic population stratification can produce false-positive results. Family-based methods have been introduced to control for this problem. This paper presents the full likelihood function for family-based association studies for nuclear families ascertained on the basis of their number of affected and unaffected children. The likelihood of a family factors into the probability of parental mating type, conditional on offspring phenotypes, times the probability of offspring genotypes given their phenotypes and the parental mating type. The first factor can be influenced by population stratification, whereas the latter factor, called the conditional likelihood, is not. The conditional likelihood is used to obtain score tests with proper size in the presence of population stratification (see also Clayton (1999) and Whittemore & Tu (2000)). Under either the additive or multiplicative model, the TDT is known to be the optimal score test when the family has only one affected child. Thus, the class of score tests explored can be considered as a general family of TDT-like procedures. The relative informativeness of the various mating types is assessed using the Fisher information, which depends on the number of affected and unaffected offspring and the penetrances. When the additive model is true, families with parental mating type Aa x Aa are most informative. Under the dominant (recessive) model, however, a family with mating type Aa x aa(AA x Aa) is more informative than a family with doubly heterozygous (Aa x Aa) parents. Because we derive explicit formulae for all components of the likelihood, we are able to present tables giving required sample sizes for dominant, additive and recessive inheritance models.

Case-Control Studies↗
PubMed2025

Sparse multitask group Lasso for genome-wide association studies.

A critical hurdle in Genome-Wide Association Studies (GWAS) involves population stratification, wherein differences in allele frequencies among subpopulations within samples are influenced by distinct ancestry. This stratification implies that risk variants may be distinct across populations with different allele frequencies. This study introduces Sparse Multitask Group Lasso (SMuGLasso) to tackle this challenge. SMuGLasso is based on MuGLasso, which formulates this problem using a multitask group lasso framework in which tasks are subpopulations, and groups are population-specific Linkage-Disequilibrium (LD)-groups of strongly correlated Single Nucleotide Polymorphisms (SNPs). The novelty in SMuGLasso is the incorporation of an additional [Formula: see text]-norm regularization for the selection of population-specific genetic variants. As MuGLasso, SMuGLasso uses a stability selection procedure to improve robustness and gap-safe screening rules for computational efficiency. We evaluate MuGLasso and SMuGLasso on simulated data sets as well as on a case-control breast cancer data set and a quantitative GWAS in Arabidopsis thaliana. We show that SMuGLasso is well suited to addressing linkage disequilibrium and population stratification in GWAS data, and show the superiority of SMuGLasso over MuGLasso in identifying population-specific SNPs. On real data, we confirm the relevance of the identified loci through pathway and network analysis, and observe that the findings of SMuGLasso are more consistent with the literature than those of MuGLasso. All in all, SMuGLasso is a promising tool for analyzing GWAS data and furthering our understanding of population-specific biological mechanisms.

Genome-Wide Association Study↗
PubMed2004

Matching strategies for genetic association studies in structured populations.

Association studies in populations that are genetically heterogeneous can yield large numbers of spurious associations if population subgroups are unequally represented among cases and controls. This problem is particularly acute for studies involving pooled genotyping of very large numbers of single-nucleotide-polymorphism (SNP) markers, because most methods for analysis of association in structured populations require individual genotyping data. In this study, we present several strategies for matching case and control pools to have similar genetic compositions, based on ancestry information inferred from genotype data for approximately 300 SNPs tiled on an oligonucleotide-based genotyping array. We also discuss methods for measuring the impact of population stratification on an association study. Results for an admixed population and a phenotype strongly confounded with ancestry show that these simple matching strategies can effectively mitigate the impact of population stratification.

Case-Control Studies↗
PubMed2005

Intercellular adhesion molecule-1 and childhood asthma.

We investigated the role of intercellular adhesion molecule-1 in childhood asthma by examining associations of functional variants at codons 29 (A --> T), 241 (G --> A), and 469 (A --> G) in Children's Health Study participants. Among African-Americans, 469G carriers had lower risk for asthma (ever asthma OR = 0.4, 95% CI 0.2-0.9) but increased risk among 29T carriers (early onset active asthma OR = 2.2, 95% CI 1.0-4.9). Protective associations with the 241A allele were observed among non-Hispanic and Hispanic whites (ever asthma OR = 0.7, 95% CI 0.6-0.9; early onset active asthma OR = 0.5, 95% CI 0.4-0.8), and these associations were not confounded by population stratification. To gauge the potential impact of confounding by population stratification, we performed analyses by ethnic group and in an independent family-based sample. Regional associations were stable across analyses. Haplotype associations of the four common haplotypes (29A/241G/469A, AGG, TGA, and AAG) with asthma showed that Hispanics with the AAG haplotype had lower asthma risk compared to carriers of two copies of AGA haplotype (OR = 0.6, 95% CI 0.4-0.9). Among non-Hispanic whites, the AAG haplotype was associated with reduced risk for active asthma. For African-Americans, who had a low frequency of the AAG haplotype, carrying one copy of the AGG haplotype was associated with a lower risk of asthma (OR = 0.3, 95% CI 0.1-0.8), as compared with two copies of the AGA haplotype. Consistent with information on variant function, the 241A and 469G variants may indicate haplotypes that are associated with reduced risk for asthma.

Adolescent↗
PubMed2004

Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations.

CONTEXT: Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D(2) dopamine receptor gene (DRD2) with substance abuse are controversial. OBJECTIVE: To determine whether susceptibility sites resided at DRD2. DESIGN: Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence. SETTING: Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China. Patients Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls). INTERVENTIONS: Genotyping for 10 SNPs by 5'-exonuclease fluorescence assays. The D' value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm. MAIN OUTCOME MEASURES: Genotype, allele, and haplotype frequencies were compared between cases and controls by chi(2) tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations. RESULTS: A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3 (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10 kb distal to the 3' end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 x 10(-22); odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 x 10(-11) for 8-SNP analysis). There was no evidence of population stratification in either population. CONCLUSIONS: These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.

Adult↗
PubMed2005

A hybrid design for studying genetic influences on risk of diseases with onset early in life.

Studies of genetic contributions to risk can be family-based, such as the case-parents design, or population-based, such as the case-control design. Both provide powerful inference regarding associations between genetic variants and risks, but both have limitations. The case-control design requires identifying and recruiting appropriate controls, but it has the advantage that nongenetic risk factors like exposures can be assessed. For a condition with an onset early in life, such as a birth defect, one should also genotype the mothers of cases and the mothers of controls to avoid potential confounding due to maternally mediated genetic effects acting on the fetus during gestation. The case-parents approach is less vulnerable than the case-mother/control-mother approach to biases due to population structure and self-selection. The case-parents approach also allows access to epigenetic phenomena like imprinting, but it cannot evaluate the role of nongenetic cofactors like exposures. We propose a hybrid design based on augmenting a set of affected individuals and their parents with a set of unaffected, unrelated individuals and their parents. The affected individuals and their parents are all genotyped, whereas only the parents of unaffected individuals are genotyped, although exposures are ascertained for both affected and unaffected offspring. The proposed hybrid design, through log-linear, likelihood-based analysis, allows estimation of the relative risk parameters, can provide more power than either the case-parents approach or the case-mother/control-mother approach, permits straightforward likelihood-ratio tests for bias due to mating asymmetry or population stratification, and admits valid alternative analyses when mating is asymmetric or when population stratification is detected.

Age of Onset↗
PubMed2004

Case-control association studies in mixed populations: correcting using genomic control.

OBJECTIVE: Case-control association studies in mixed populations can result in spurious disease-marker associations if subpopulation disease prevalence and marker frequencies both differ. Genomic control (GC) uses neutral loci to correct for spurious association (due to population stratification), but how well this works remains undetermined. METHODS: We simulated and mixed populations with different disease and marker frequencies but without marker-disease association. We generated case-control datasets, calculated the chi2 for disease association with each marker, and applied two GC procedures, dividing by the mean chi2 or median-chi2/0.456. RESULTS: Corrections became conservative (false positive rate [FPR] <5%) with increasing subpopulation prevalence and marker differences. The mean correction resulted in FPRs close to 5% at average subpopulation allele frequency differences <0.26, but inclusion of just a few markers with large frequency differences resulted in conservative FPRs. FPRs from the median correction were mostly conservative but became anticonservative when a few markers with large frequency differences were included. CONCLUSION: GC can both lead to a notable loss of power to detect a true association (conservative) in many circumstances or may fail to eliminate the spurious associations (anticonservative). The mean correction factor is useful in certain situations to correct population stratification, but it is difficult to know when those situations exist.

Alleles↗
PubMed2003

Control of confounding of genetic associations in stratified populations.

To control for hidden population stratification in genetic-association studies, statistical methods that use marker genotype data to infer population structure have been proposed as a possible alternative to family-based designs. In principle, it is possible to infer population structure from associations between marker loci and from associations of markers with the trait, even when no information about the demographic background of the population is available. In a model in which the total population is formed by admixture between two or more subpopulations, confounding can be estimated and controlled. Current implementations of this approach have limitations, the most serious of which is that they do not allow for uncertainty in estimations of individual admixture proportions or for lack of identifiability of subpopulations in the model. We describe methods that overcome these limitations by a combination of Bayesian and classical approaches, and we demonstrate the methods by using data from three admixed populations--African American, African Caribbean, and Hispanic American--in which there is extreme confounding of trait-genotype associations because the trait under study (skin pigmentation) varies with admixture proportions. In these data sets, as many as one-third of marker loci show crude associations with the trait. Control for confounding by population stratification eliminates these associations, except at loci that are linked to candidate genes for the trait. With only 32 markers informative for ancestry, the efficiency of the analysis is 70%. These methods can deal with both confounding and selection bias in genetic-association studies, making family-based designs unnecessary.

Bayes Theorem↗
PubMed1999

Asymptotic bias and efficiency in case-control studies of candidate genes and gene-environment interactions: basic family designs.

Case-control designs that use population controls are compared with those that use controls selected from their relatives (i.e., siblings, cousins, or "pseudosibs" based on parental alleles) for estimating the effect of candidate genes and gene-environment interactions. The authors first evaluate the asymptotic bias in relative risk estimates resulting from using population controls when there is confounding due to population stratification. Using siblings or pseudosibs as controls completely addresses this issue, whereas cousins provide only partial protection from population stratification. Next, they show that the conventional conditional likelihood for matched case-control studies can give asymptotically biased effect estimates when applied to the pseudosib approach; the asymptotic bias is toward the null and disappears with disease rarity. They show how to reparameterize the pseudosib likelihood so this approach gives consistent effect estimates. They then show that the designs using population or pseudosib controls are generally the most efficient for estimating the main effect of a candidate gene, followed in efficiency by the design using cousins. Finally, they show that the design using sibling controls can be quite efficient when studying gene-environment interactions. In addition to asymptotic bias and efficiency issues, family-based designs might benefit from a higher motivation to participate among cases' relatives, but these designs have the disadvantage that many potential cases will be excluded from study by having no available controls.

Bias↗
PubMed2004

A polymorphism of the beta1-adrenergic receptor is associated with low extraversion.

BACKGROUND: We examined the possibility that allelic variation leading to alterations in beta(1)-adrenergic function might be present in persons with elevated social anxiety-related traits. METHODS: A sample of 504 undergraduate college students were phenotyped on a personality inventory (the NEO-Personality Inventory-Revised) and measures of shyness and social anxiety and genotyped for two beta(1) adrenergic (ADRB1 gene) polymorphisms: a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly). We hypothesized that the Gly49 variant (thought to be functional), but not variation at Arg389Gly, would be associated with (low) extraversion and shyness. We evaluated the potential for population stratification artifact by genotyping a set of 36 unlinked, highly polymorphic markers previously demonstrated to sufficiently distinguish the ancestry of major American populations. RESULTS: Presence of a Gly49 allele was associated with an increased odds of having low or very low extraversion (odds ratio = 1.68, 95% confidence interval 1.05-2.71). The Arg389Gly polymorphism, although in tight linkage disequilibrium (D' = -1.00) with Ser49Gly, was not significantly associated with level of extraversion. Formal testing showed that population structure did not explain the findings. CONCLUSIONS: The Ser49Gly functional polymorphism in the beta(1) adrenergic receptor might explain some of the population variance in extraversion and related personality traits. Population structure was excluded as an explanation for these findings. We used a sufficient marker set to exclude possible population stratification artifact. These findings should be replicated and extended to the study of psychiatric disorders marked by low extraversion, namely social phobia and other phobic disorders.

Adolescent↗
PubMed2002

Genetic association studies: design, analysis and interpretation.

This paper provides a review of the design and analysis of genetic association studies. In case control studies, the different contingency tables and their relationships to the underlying genetic model are defined. Population stratification is discussed, with suggested methods to identify and correct for the effect. The transmission disequilibrium test is provided as an alternative family-based test, which is robust to population stratification. The relative benefits of each analysis are summarised.

Case-Control Studies↗
PubMed2003

The insulin gene variable number tandem repeat class I/III polymorphism is in linkage disequilibrium with birth weight but not Type 2 diabetes in the Pima population.

The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (-23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring "trio" design was used to assess parent-of-origin effects and population stratification. The presence of the -23Hph1 T-allele was associated with lower birth weight (n = 192; -140 g per copy of the T-allele; P = 0.04), even after adjustment for effects of population stratification (P = 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: -250 g, P = 0.05; maternally transmitted: -111 g, P = 0.43), but this difference was not statistically significant (P = 0.50). The -23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P = 0.009), which family-based association analysis suggested was attributable to population structure (P = 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P = 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was found between -23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight.

Adult↗