Genetic variants on the X-chromosome could potentially play an important role in some complex traits. However, development of methods for detecting association with X-linked markers has lagged behind that for autosomal markers. We propose methods for case-control association testing with X-chromosome markers in samples with related individuals. Our method, XM, appropriately adjusts for both correlation among relatives and male-female allele copy number differences. Features of XM include: (1) it is applicable to and computationally feasible for completely general combinations of family and case-control designs; (2) it allows for both unaffected controls and controls of unknown phenotype to be included in the same analysis; (3) it can incorporate phenotype information on relatives with missing genotype data; and (4) it adjusts for sex-specific trait prevalence values. We propose two other tests, Xχ and XW, which can also be useful in certain contexts. We derive the best linear unbiased estimator of allele frequency, and its variance, for X-linked markers. In simulation studies with related individuals, we demonstrate the power and validity of the proposed methods. We apply the methods to X-chromosome association analysis of (1) asthma in a Hutterite sample and (2) alcohol dependence in the GAW 14 COGA data. In analysis (1), we demonstrate computational feasibility of XM and the applicability of our robust variance estimator. In analysis (2), we detect significant association, after Bonferroni correction, between alcohol dependence and SNP rs979606 in the MAOA gene, where this gene has previously been found to be associated with substance abuse and antisocial behavior.

The two alleles an individual carries at a locus are identical by descent (ibd) if they have descended from a single ancestral allele in a reference population, and the probability of such identity is the inbreeding coefficient of the individual. Inbreeding coefficients can be predicted from pedigrees with founders constituting the reference population, but estimation from genetic data is not possible without data from the reference population. Most inbreeding estimators that make explicit use of sample allele frequencies as estimates of allele probabilities in the reference population are confounded by average kinships with other individuals. This means that the ranking of those estimates depends on the scope of the study sample and we show the variation in rankings for common estimators applied to different subdivisions of 1000 Genomes data. Allele-sharing estimators of within-population inbreeding relative to average kinship in a study sample, however, do have invariant rankings across all studies including those individuals. They are unbiased with a large number of SNPs. We discuss how allele sharing estimates are the relevant quantities for a range of empirical applications.

Background Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multi-ethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. Objective Conduct a genome-wide association study (GWAS) of heart rate (HR) and its variability in the Hispanic Community Health Study / Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n=13,767). Methods We estimated HR (beats/min), the standard deviation of normal-to-normal inter-beat intervals (SDNN, ms), and the root mean squared difference in successive, normal-to-normal inter-beat intervals (RMSSD, ms) from resting, standard twelve-lead electrocardiograms. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P<5×10-8) or suggestive (P<10-6) significance thresholds. Results Two genome-wide significant SNPs replicated in a European ancestry cohort, one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. Conclusions This first GWAS of HRV and HR in Hispanics/Latinos underscores the potential for even modestly-sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

Supplementary data are available at Bioinformatics online.