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.

We performed genome-wide tests for association between haplotype clusters and each of 9 metabolic traits in a cohort of 5402 Northern Finnish individuals genotyped for 330 000 single-nucleotide polymorphisms. The metabolic traits were body mass index, C-reactive protein, diastolic blood pressure, glucose, high-density lipoprotein (HDL), insulin, low-density lipoprotein (LDL), systolic blood pressure, and triglycerides. Haplotype clusters were determined using Beagle. There were LDL-associated clusters in the chromosome 4q13.3-q21.1 region containing the albumin (ALB) and platelet factor 4 (PF4) genes. This region has not been associated with LDL in previous genome-wide association studies. The most significant haplotype cluster in this region was associated with 0.488 mmol/l higher LDL (95% CI: 0.361-0.615 mmol/l, P-value: 6.4 Â 10 À14 ). We also observed three previously reported associations: Chromosome 16q13 with HDL, chromosome 1p32. INTRODUCTIONThe identification of genetic factors that influence quantitative traits such as low-density lipoprotein (LDL) has clinical importance. For example, higher LDL levels are associated with increased risk of cardiovascular health disease, and the discovery of the association between PCSK9 mutations and LDL led to the development of PCSK9 inhibitors as a novel class of LDL-reducing drugs. 1 Notably, in the cohort study that found the LDL-associated PCSK9 mutations, each mutation was present in fewer than 2% of study individuals. 2 The standard single-SNP analysis commonly employed in genome-wide association studies (GWAS) has low power for detecting such low frequency causal variants. By employing haplotypic analysis in combination with single-SNP analysis, we can improve power above that of single-SNP analysis alone for detecting causal variants with low minor allele frequency. 3 The standard approach for association analysis of genome-wide single-nucleotide polymorphism (SNP) array data in population samples is to test each SNP individually for association with the trait. This approach can have high power to detect an ungenotyped causal variant when the causal variant is common and correlated with one or more genotyped variants on the array. However, the single-SNP approach has lower power to detect low frequency ungenotyped causal variants. 3 To improve power for low frequency variants, one could impute them and test for association with the trait, but imputation of low frequency variants suffers from poor accuracy. 4 Moreover, variants that are unique to the population of interest

Background: Histologic grading using the Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) system is not universally accepted as applicable to malignant peripheral nerve sheath tumor (MPNST), as its prognostic value is not well established. Methods:We retrospectively evaluated 99 cases of MPNST to investigate any association between the outcomes overall survival (OS) and progression-free survival (PFS), and predictor variables FNCLCC grade, clinical setting, tumor location, and tumor size at diagnosis using multivariable Cox proportional hazard analysis.Results: Univariable and multivariable analysis demonstrate a statistically significant association between FNCLCC grade and both OS and PFS when comparing tumors by histologic grade. Of note, no deaths were observed in patients with grade 1 MPNST. Other variables associated with unfavorable outcomes include fragmented resection and primary site, with tumors in the extremities having favorable OS, but not PFS, when compared with those in truncal locations. Tumors in the head and neck had favorable PFS, but not OS, compared with those in the trunk. No statistically significant differences in OS or PFS were observed when comparing patient age and sex, tumor size at diagnosis, clinical setting (primary vs. type-1 neurofibromatosis vs. radiation associated) or history of neoadjuvant therapy. Interobserver agreement for FNCLCC grading of these tumors was considered good (S* = 0.77, 95% confidence interval: 0.71-0.84).Conclusions: Association between FNCLCC grading and survival outcomes in MPNST suggests potential value to routinely grading these neoplasms. However, the subjectivity of the grading system, particularly when assigning a tumor differentiation score, may pose a challenge, especially in low and intermediate grade lesions.