Trichotillomania comorbidity in a sample enriched for familial obsessive-compulsive disorder.

BACKGROUND: This study addresses the strength of associations between trichotillomania (TTM) and other DSM-IV Axis I conditions in a large sample (n = 2606) enriched for familial obsessive-compulsive disorder (OCD), to inform TTM classification. METHODS: We identified participants with TTM in the Johns Hopkins OCD Family Study (153 families) and the OCD Collaborative Genetics Study, a six-site genetic linkage study of OCD (487 families). We used logistic regression (with generalized estimating equations) to assess the strength of associations between TTM and other DSM-IV disorders. RESULTS: TTM had excess comorbidity with a number of conditions from different DSM-IV chapters, including tic disorders, alcohol dependence, mood disorders, anxiety disorders, impulse-control disorders, and bulimia nervosa. However, association strengths (odds ratios) were highest for kleptomania (6.6), pyromania (5.8), OCD (5.6), skin picking disorder (4.4), bulimia nervosa (3.5), and pathological nail biting (3.4). CONCLUSIONS: TTM is comorbid with a number of psychiatric conditions besides OCD, and it is strongly associated with other conditions involving impaired impulse control. Though DSM-5 includes TTM as an OCD-related disorder, its comorbidity pattern also emphasizes the impulsive, appetitive aspects of this condition that may be relevant to classification.

Gene-gene interaction of single nucleotide polymorphisms in 16p13.3 may contribute to the risk of non-syndromic cleft lip with or without cleft palate in Chinese case-parent trios.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with a complex and heterogeneous etiology. A recent genome-wide association study (GWAS) among Chinese populations has identified a new region at 16p13.3 as being associated with NSCL/P, which requires further replication. Here, we attempted to replicate and further clarify the genetic association between this region and NSCL/P, as well as testing for potential gene-gene (G × G) and gene-environment (G × E) interactions. We conducted transmission disequilibrium tests on 69 single nucleotide polymorphisms (SNPs) mapping to 16p13.3 among 806 Chinese case-parent trios ascertained through an international consortium where a GWAS of oral clefts was conducted. G × G, as well as G × E interactions involving maternal environmental tobacco smoke (ETS) and multivitamin supplementation, were explored using conditional logistic regression model. We applied Cordell's method as implemented in the R package TRIO to test for possible interactions. While no SNPs showed evidence of linkage and association with NSCL/P after Bonferroni correction, we found signals of G × G interactions between SNPs in 16p13.3. Nine pairs of SNP-SNP interactions attained significance after Bonferroni correction, among which the most significant interaction was found between rs2072346 (ADCY9) and rs11646137 (intergenic region, P = 7.2 × 10-5 ). Linkage disequilibrium (LD) analysis revealed only low level of LD between these SNPs. This study failed to confirm the significant association between SNPs within 16p13.3 and the risk of NSCL/P, but underlined the importance of taking into account potential G × G interactions for the genetic association analysis of NSCL/P.

Simultaneous estimation of the locations and effects of multiple disease loci in case-control studies.

The genetic basis of complex diseases often involves multiple causative loci. Under such a disease etiology, assuming one disease locus in linkage disequilibrium mapping is likely to induce bias and lead to efficiency loss in disease locus estimation. An approach is needed for simultaneously localizing multiple functional loci within the same region. However, due to the increasing number of parameters accompanying disease loci, these estimates can be computationally infeasible. To circumvent this problem, we propose to estimate the main and two-adjacent-locus joint effects and a nuisance parameter at the disease loci separately through a linear approximation. Estimates of the genetic effects are entered into a generalized estimating equation to estimate disease loci, and the procedure is conducted iteratively until convergence. The proposed method provides estimates and confidence intervals (CIs) for the disease loci, the genetic main effects, and the joint effects of two adjacent disease loci, with the CIs for the disease loci providing useful regions for further fine-mapping. We apply the proposed approach to a data example of case-control studies. Results of the simulations and data example suggest that the developed method performs well in terms of bias, variance, and coverage probability under scenarios with up to three disease loci.

Body mass index and risk of incident hypertension over the life course: the Johns Hopkins Precursors Study.

BACKGROUND: The obesity-hypertension link over the life course has not been well characterized, although the prevalence of obesity and hypertension is increasing in the United States. METHODS AND RESULTS: We studied the association of body mass index (BMI) in young adulthood, into middle age, and through late life with risk of developing hypertension in 1132 white men of The Johns Hopkins Precursors Study, a prospective cohort study. Over a median follow-up period of 46 years, 508 men developed hypertension. Obesity (BMI ≥30 kg/m(2)) in young adulthood was strongly associated with incident hypertension (hazard ratio, 4.17; 95% confidence interval, 2.34-7.42). Overweight (BMI 25 to <30 kg/m(2)) also signaled increased risk (hazard ratio, 1.58; 95% confidence interval, 1.28-1.96). Men of normal weight at age 25 years who became overweight or obese at age 45 years were at increased risk compared with men of normal weight at both times (hazard ratio, 1.57; 95% confidence interval, 1.20-2.07), but not men who were overweight or obese at age 25 years who returned to normal weight at age 45 years (hazard ratio, 0.91; 95% confidence interval, 0.43-1.92). After adjustment for time-dependent number of cigarettes smoked, cups of coffee taken, alcohol intake, physical activity, parental premature hypertension, and baseline BMI, the rate of change in BMI over the life course increased the risk of incident hypertension in a dose-response fashion, with the highest risk among men with the greatest increase in BMI (hazard ratio, 2.52; 95% confidence interval, 1.82-3.49). CONCLUSIONS: Our findings underscore the importance of higher weight and weight gain in increasing the risk of hypertension from young adulthood through middle age and into late life.

The FGF and FGFR Gene Family and Risk of Cleft Lip With or Without Cleft Palate.

Background : Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods : We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results : Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion : Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.

[Association study for gene polymorphism of folic acid/homocysteine metabolic pathway and nonsyndromic cleft lip with or without cleft palate in Chinese populations].

OBJECTIVE: To explore the association between 18 candidate genes encoding enzymes on the folate/homocysteine metabolism pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) in Chinese populations. METHODS: A total of 806 NSCL/P trios were drawn by an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate genes affecting risks to NSCL/P. The transmission disequilibrium test (TDT) was used for deviation from Mendelian expectations for 257 SNPs in 18 folate/homocysteine metabolism-related genes. The interactions between markers in these gene and environmental risk factors were also tested using conditional Logistic regressions. RESULTS: Although four SNPs (rs6428977, rs12060264, rs7730643 and rs4920037) showed nominal significant association with NSCL/P in the TDT on 806 NSCL/P trios (P<0.05), no significant evidence of linkage and association remained in all the SNPs after Bonferroni correction. Similar tests for interactions between genes and maternal smoking, environmental tobacco smoke, alcohol consumption and multi-vitamin supplementation during pregnancy did not attain statistical significance after correction for multiple comparisons. CONCLUSION: Folate/homocysteine metabolism-related genes could not influence the risk of NSCL/P.

Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP.

Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia.

Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.

Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate.

This study examined the association between 49 markers in the Runt-related transcription factor 2 (RUNX2) gene and nonsyndromic cleft lip with/without cleft palate (CL/P) among 326 Chinese case-parent trios, while considering gene-environment (GxE) interaction and parent-of-origin effects. Five single-nucleotide polymorphisms (SNPs) showed significant evidence of linkage and association with CL/P and these results were replicated in an independent European sample of 825 case-parent trios. We also report compelling evidence for interaction between markers in RUNX2 and environmental tobacco smoke (ETS). Although most marginal SNP effects (i.e., ignoring maternal exposures) were not statistically significant, eight SNPs were significant when considering possible interaction with ETS when testing for gene (G) and GxE interaction simultaneously or when considering GxE alone. Independent samples from European populations showed consistent evidence of significant GxETS interaction at two SNPs (rs6904353 and rs7748231). Our results suggest genetic variation in RUNX2 may influence susceptibility to CL/P through interacting with ETS.

Detection of SNP-SNP interactions in trios of parents with schizophrenic children.

Schizophrenia (SZ) is a heritable and complex psychiatric disorder with an estimated worldwide prevalence of about 1%. Research on the risk factors for SZ has thus far yielded few clues to causes, but has pointed to a heterogeneous etiology that likely involves multiple genes and gene-environment interactions. In this manuscript, we apply a novel method (trio logic regression, Li et al., 2009) to case-parent trio data from a SZ candidate gene study conducted on families of Ashkenazi Jewish descent, and demonstrate the method's ability to detect multi-gene models for SZ risk in the family-based design. In particular, we demonstrate how this method revealed a genotype-phenotype association that includes an allele without marginal effect.

Hypothesis testing in a mixture case-control model.

We consider a problem of testing mixture proportions using two-sample data, one from group one and the other from a mixture of groups one and two with unknown proportion, λ, for being in group two. Various statistical applications, including microarray study, infectious epidemiological studies, case-control studies with contaminated controls, clinical trials allowing "nonresponders," genetic studies for gene mutation, and fishery applications can be formulated in this setup. Under the assumption that the log ratio of probability (density) functions from the two groups is linear in the observations, we propose a generalized score test statistic to test the mixture proportion. Under some regularity conditions, it is shown that this statistic converges to a weighted chi-squared random variable under the null hypothesis of λ= 0, where the weight depends only on the sampling fraction of both groups. The permutation method is used to provide more reliable finite sample approximation. Simulation results and two real data applications are presented.

Likelihood ratio testing for admixture models with application to genetic linkage analysis.

We consider likelihood ratio tests (LRT) and their modifications for homogeneity in admixture models. The admixture model is a two-component mixture model, where one component is indexed by an unknown parameter while the parameter value for the other component is known. This model is widely used in genetic linkage analysis under heterogeneity in which the kernel distribution is binomial. For such models, it is long recognized that testing for homogeneity is nonstandard, and the LRT statistic does not converge to a conventional χ(2) distribution. In this article, we investigate the asymptotic behavior of the LRT for general admixture models and show that its limiting distribution is equivalent to the supremum of a squared Gaussian process. We also discuss the connection and comparison between LRT and alternative approaches such as modifications of LRT and score tests, including the modified LRT (Fu, Chen, and Kalbfleisch, 2006, Statistica Sinica 16, 805-823). The LRT is an omnibus test that is powerful to detect general alternative hypotheses. In contrast, alternative approaches may be slightly more powerful to detect certain type of alternatives, but much less powerful for others. Our results are illustrated by simulation studies and an application to a genetic linkage study of schizophrenia.

Separation anxiety disorder in OCD.

BACKGROUND: A history of separation anxiety disorder (SAD) is frequently reported by patients with obsessive-compulsive disorder (OCD). The purpose of this study was to determine if there are clinical differences between OCD-affected individuals with, versus without, a history of SAD. METHODS: Using data collected during the OCD Collaborative Genetic Study, we studied 470 adult OCD participants; 80 had a history of SAD, whereas 390 did not. These two groups were compared as to onset and severity of OCD, lifetime prevalence of Axis I disorders, and number of personality disorder traits. RESULTS: OCD participants with a history of SAD were significantly younger than the non-SAD group (mean, 34.2 versus 42.2 years; P<.001). They had an earlier age of onset of OCD symptoms (mean, 8.0 versus 10.5 years; P<.003) and more severe OCD, as measured by the Yale-Brown Obsessive Compulsive Scale (mean, 27.5 versus 25.0; P<.005). In addition, those with a history of SAD had a significantly greater lifetime prevalence of agoraphobia (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.4-4.6, P<.003), panic disorder (OR = 1.84, CI = 1.03-3.3 P<.04), social phobia (OR = 1.69, CI 1.01-2.8, P<.048), after adjusting for age at interview, age at onset of OCD, and OCD severity in logistic regression models. There was a strong relationship between the number of dependent personality disorder traits and SAD (adjusted OR = 1.42, CI = 1.2-1.6, P<.001). CONCLUSIONS: A history of SAD is associated with anxiety disorders and dependent personality disorder traits in individuals with OCD.

Familial aggregation of panic disturbances in Parkinson's disease.

Panic disorder has an elevated prevalence in Parkinson's disease (PD). To explore the basis for this co-occurrence, the familial aggregation of panic disorder was examined in patients with PD. Probands and relatives of patients with PD and panic disorder (PD-PANIC; N=20, N=115) and control probands with PD and no active psychiatric illness (PD-NA; N=17, N=108) were interviewed by phone, using a structured interview to determine panic status. Lifetime prevalence of panic and "panic-like" disorders was higher in PD-PANIC than in PD-NA relatives. Panic and "panic-like" disorders are familial disorders in PD.

Incorporating covariates into multipoint association mapping in the case-parent design.

BACKGROUND/AIMS: To improve the efficiency of disease locus localization in association mapping using case-parent designs and to assess or account for the main covariate effects and gene-covariate interaction effects, while localizing the disease locus. METHODS: The present study extends a multipoint fine-mapping approach to incorporate covariates into the association mapping of case-parent designs through parametric and non-parametric modeling. This approach is based on the expected preferential-allele-transmission statistics for transmission from either parent to an affected child. RESULTS: Simulation studies indicate that the efficiency in estimating the disease locus increases considerably when incorporating a covariate associated with the disease. This is especially true when the genetic effect of the disease locus is small. The proposed approach was applied to a young-onset hypertension data sample. The relative efficiency of estimating the locus of young-onset hypertension increases 110-fold after incorporating triglyceride into the association mapping while localizing the disease variant in the lipoprotein lipase gene in the non-parametric model. By incorporating the information of SNP variants into the fine-mapping, the proposed method further assesses the gene-gene interactions between the SNP and the disease locus. CONCLUSION: With the incorporation of covariates, the proposed method cannot only improve efficiency in estimating disease loci, but can also elucidate the etiology of a complex disease.

Linkage and association on 8p21.2-p21.1 in schizophrenia.

In the past decade, we and others have consistently reported linkage to a schizophrenia (SZ) susceptibility region on chromosome 8p21. Most recently, in the largest SZ linkage sample to date, a multi-site international collaboration performed a SNP-based linkage scan (~6,000 SNPs; 831 pedigrees; 121 from Johns Hopkins (JHU)), that showed the strongest evidence for linkage in a 1 Mb region of chr 8p21 from rs1561817 to rs9797 (Z(max) = 3.22, P = 0.0004) [Holmans et al. 2009. Mol Psychiatry]. We have investigated this 8p21 peak region further in two ways: first by linkage and family-based association in 106 8p-linked European-Caucasian (EUC) JHU pedigrees using 1,402 SNPs across a 4.4 Mb region surrounding the peak; second, by an independent case-control association study in the genetically more homogeneous Ashkenazim (AJ) (709 cases, 1,547 controls) using 970 SNPs in a further narrowed 2.8 Mb region. Family-based association analyses in EUC pedigrees and case-control analyses in AJ samples reveal significant associations for SNPs in and around DPYSL2 and ADRA1A, candidate genes previously associated with SZ in our work and others. Further, several independent gene expression studies have shown that DPYSL2 is differentially expressed in SZ brains [Beasley et al. 2006. Proteomics 6(11):3414­3425; Edgar et al. 2000. Mol Psychiatry 5(1):85­90; Johnston-Wilson et al. 2000. Mol Psychiatry 5(2):142­149] or in response to psychosis-inducing pharmaceuticals [Iwazaki et al. 2007. Proteomics 7(7):1131­1139; Paulson et al. 2004. Proteomics 4(3):819­825]. Taken together, this work further supports DPYSL2 and the surrounding genomic region as a susceptibility locus for SZ.

Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder.

SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD). Several independent research groups have reported significant associations between OCD and single nucleotide polymorphisms (SNPs) in this gene. Previously, we evaluated 13 SNPs in, or near, SLC1A1 and reported a strong association signal with rs301443, a SNP 7.5 kb downstream of the gene [Shugart et al. (2009); Am J Med Genet Part B 150B:886­892]. The aims of the current study were first, to further investigate this finding by saturating the region around rs301443; and second, to explore the entire gene more thoroughly with a dense panel of SNP markers. We genotyped an additional 111 SNPs in or near SLC1A1, covering from 9 kb upstream to 84 kb downstream of the gene at average spacing of 1.7 kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families.We found that none of the surrounding markers were in linkage disequilibrium with rs301443, nor were any associated with OCD. We also found that SNP rs4740788, located about 8.8 kb upstream of the gene, was associated with OCD in all families (P = 0.003) and in families with male affecteds (P = 0.002). A three-SNP haplotype (rs4740788­rs10491734­rs10491733) was associated with OCD in the total sample (P = 0.00015) and in families with male affecteds (P = 0.0007). Although of nominal statistical significance considering the number of comparisons, these findings provide further support for the involvement of SLC1A1 in the pathogenesis of OCD.

Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate.

Although multiple genes have been identified as genetic risk factors for isolated, non-syndromic cleft lip with/without cleft palate (CL/P), a complex and heterogeneous birth defect, interferon regulatory factor 6 gene (IRF6) is one of the best documented genetic risk factors. In this study, we tested for association between markers in IRF6 and CL/P in 326 Chinese case-parent trios, considering gene-environment interaction for two common maternal exposures, and parent-of-origin effects. CL/P case-parent trios from three sites in mainland China and Taiwan were genotyped for 22 single nucleotide polymorphisms (SNPs) in IRF6. The transmission disequilibrium test was used to test for marginal effects of individual SNPs. We used PBAT to screen the SNPs and haplotypes for gene-environment (G×E) interaction and conditional logistic regression models to quantify effect sizes for SNP-environment interaction. After Bonferroni correction, 14 SNPs showed statistically significant association with CL/P. Evidence of G×E interaction was found for both maternal exposures, multivitamin supplementation and environmental tobacco smoke (ETS). Two SNPs showed evidence of interaction with multivitamin supplementation in conditional logistic regression models (rs2076153 nominal P=0.019, rs17015218 nominal P=0.012). In addition, rs1044516 yielded evidence for interaction with maternal ETS (nominal P=0.041). Haplotype analysis using PBAT also suggested interaction between SNPs in IRF6 and both multivitamin supplementation and ETS. However, no evidence for maternal genotypic effects or significant parent-of-origin effects was seen in these data. These results suggest IRF6 gene may influence risk of CL/P through interaction with multivitamin supplementation and ETS in the Chinese population.

Incorporation of covariates in simultaneous localization of two linked loci using affected relative pairs.

BACKGROUND: Many dichotomous traits for complex diseases are often involved more than one locus and/or associated with quantitative biomarkers or environmental factors. Incorporating these quantitative variables into linkage analysis as well as localizing two linked disease loci simultaneously could therefore improve the efficiency in mapping genes. We extended the robust multipoint Identity-by-Descent (IBD) approach with incorporation of covariates developed previously to simultaneously estimate two linked loci using different types of affected relative pairs (ARPs). RESULTS: We showed that the efficiency was enhanced by incorporating a quantitative covariate parametrically or non-parametrically while localizing two disease loci using ARPs. In addition to its help in identifying factors associated with the disease and in improving the efficiency in estimating disease loci, this extension also allows investigators to account for heterogeneity in risk-ratios for different ARPs. Data released from the collaborative study on the genetics of alcoholism (COGA) for Genetic Analysis Workshop 14 (GAW 14) were used to illustrate the application of this extended method. CONCLUSIONS: The simulation studies and example illustrated that the efficiency in estimating disease loci was demonstratively enhanced by incorporating a quantitative covariate and by using all relative pairs while mapping two linked loci simultaneously.

A pseudolikelihood approach for assessing genetic association in case-control studies with unmeasured population structure.

The case-control study design is one of the main tools for detecting associations between genetic markers and diseases. It is well known that population substructure can lead to spurious association between disease status and a genetic marker if the prevalence of disease and the marker allele frequency vary across subpopulations. In this paper, we propose a novel statistical method to estimate the association in case-control studies with unmeasured population substructure. The proposed method takes two steps. First, the information on genomic markers and disease status is used to infer the population substructure; second, the association between the disease and the test marker adjusting for the population substructure is modeled and estimated parametrically through polytomous logistic regression. The performance of the proposed method, relative to the existing methods, on bias, coverage probability and computational time, is assessed through simulations. The method is applied to an end-stage renal disease study in African Americans population.