Hierarchical modeling in association studies of multiple phenotypes

The genetic study of disease-associated phenotypes has become common because such phenotypes are often easier to measure and in many cases are under greater genetic control than the complex disease itself. Some disease-associated phenotypes are rare, however, making it difficult to evaluate their effects due to small informative sample sizes. In addition, analyzing numerous phenotypes introduces the issue of multiple comparisons. To address these issues, we have developed a hierarchical model (HM) for multiple phenotypes that provides more accurate effect estimates with a lower false-positive rate. We evaluated the validity and power of HM in association studies of multiple phenotypes using randomly selected cases and controls from the simulated data set in the Genetic Analysis Workshop 14. In particular, we first analyzed the association between each of the 12 subclinical phenotypes and single-nucleotide polymorphisms within the known causal loci using a conventional logistic regression model (LRM). Then we added a second-stage model by regressing all of the logistic coefficients of the phenotypes obtained from LRM on a Z matrix that incorporates the clinical correlation of the phenotypes. Specially, the 12 phenotypes were grouped into 3 clusters: 1) communally shared emotions; 2) behavioral related; and 3) anxiety related. A semi-Bayes HM effect estimate for each phenotype was calculated and compared with those from LRM. We observed that using HM to evaluate the association between SNPs and multiple related phenotypes slightly increased power for detecting the true associations and also led to fewer false-positive results

An empirical evaluation of the common disease-common variant hypothesis

While genome-wide linkage studies have been successful in mapping variants underlying rare monogenic disorders, genome-wide association studies may be more appropriate for detecting common variants of modest effects that underlie common disorders. To this end, we were interested in determining whether genetic variants associated with a phenotype differed depending on whether they were within or outside of regions linked to the phenotype. In particular, we compared allele frequencies and effect sizes between associated single-nucleotide polymorphisms within and outside of linkage regions using the Genetic Analysis Workshop 15 Problem 1. We did not find any statistically significant differences between these two sets. However, our power calculations show that these results may be inconclusive

Interprofessional student-run primary health clinics: implications for pharmacy education in Scotland.

Introduction Interprofessional student run primary health care clinics have been a flagship model of health professional education in Canada for many years. The purpose of this study was to determine if there is support for implementing this educational model in the United Kingdom and to highlight the implications for pharmacy education in Scotland. Method A cross-sectional postal survey of 3000 randomly selected citizens of Aberdeen city and shire, Scotland, aged 18 years and over. Results Out of the 824 questionnaires that were returned (response rate 27.5%) over half of respondents (62.4%; n=514) would consider accessing healthcare from a student led, walk in service. The range of services they expect to see include general health checks (60%; n=494); help for sexually transmitted diseases (57.5%; n=474); weight management (56.8%; n=468); smoking cessation (54.4%; n=448) and drug misuse services (47.2%; n=387). Concerns raised pertained to student ability; suitability for children and accessibility. Many comments pertained to the improvement of the current system by offering after-hours care. Discussion The positive response from the general public towards an interprofessional student run primary health care clinic in Aberdeen, suggest that this Canadian model of interdisciplinary health professional education would likely be a successful addition to the pharmacy curriculum in Scotland

A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia.

Inguinal hernia repair is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop inguinal hernias. We perform a genome-wide association analysis of surgically confirmed inguinal hernias in 72,805 subjects (5,295 cases and 67,510 controls) and confirm top associations in an independent cohort of 92,444 subjects with self-reported hernia repair surgeries (9,701 cases and 82,743 controls). We identify four novel inguinal hernia susceptibility loci in the regions of EFEMP1, WT1, EBF2 and ADAMTS6. Moreover, we observe expression of all four genes in mouse connective tissue and network analyses show an important role for two of these genes (EFEMP1 and WT1) in connective tissue maintenance/homoeostasis. Our findings provide insight into the aetiology of hernia development and highlight genetic pathways for studies of hernia development and its treatment

A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a leading cause of blindness. IOP heritability has been estimated to up to 67%, and to date only 11 IOP loci have been reported, accounting for 1.5% of IOP variability. Here, we conduct a genome-wide association study of IOP in 69,756 untreated individuals of European, Latino, Asian, and African ancestry. Multiple longitudinal IOP measurements were collected through electronic health records and, in total, 356,987 measurements were included. We identify 47 genome-wide significant IOP-associated loci (P < 5 × 10-8); of the 40 novel loci, 14 replicate at Bonferroni significance in an external genome-wide association study analysis of 37,930 individuals of European and Asian descent. We further examine their effect on the risk of glaucoma within our discovery sample. Using longitudinal IOP measurements from electronic health records improves our power to identify new variants, which together explain 3.7% of IOP variation

The UCSD Radio-Selected Quasar Survey for Damped Lyman alpha System

As large optical quasar surveys for damped Lya become a reality and the study of star forming gas in the early Universe achieves statistical robustness, it is now vital to identify and quantify the sources of systematic error. Because the nature of optically-selected quasar surveys makes them vulnerable to dust obscuration, we have undertaken a radio-selected quasar survey for damped Lya systems to address this bias. We present the definition and results of this survey. We then combine our sample with the CORALS dataset to investigate the HI column density distribution function f(N) of damped Lya systems toward radio-selected quasars. We find that f(N) is well fit by a power-law f(N) = k_1 N^alpha_1, with log k_1 = 22.90 and alpha_1 = -2.18. This power-law is in excellent agreement with that of optically-selected samples at low N(HI), an important yet expected result given that obscuration should have negligible effect at these gas columns. However, because of the relatively small size of the radio-selected sample, 26 damped Lya systems in 119 quasars, f(N) is not well constrained at large N(HI) and the first moment of the HI distribution function, Omega_g, is, strictly speaking, a lower limit. The power-law is steep enough, however, that extrapolating it to higher column densities implies only a modest, logarithmic increase in Omega_g. The radio-selected value of Omega_g = 1.15 x 10^-3, agrees well with the results of optically-selected surveys. While our results indicate that dust obscuration is likely not a major issue for surveys of damped Lya systems, we estimate that a radio-selected sample of approximately 100 damped Lya systems will be required to obtain the precision necessary to absolutely confirm an absence of dust bias.Comment: 12 pages, 9 Figures. Accepted to ApJ April 11, 200

Genetic variation in the SIM1 locus is associated with erectile dysfunction.

Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function