Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p &lt; 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Early Improvements in insulin sensitivity and inflammatory markers are induced by pravastatin in nondiabetic subjects with hypercholesterolemia

Background: Statins may improve lipid profiles and inflammation-associated biomarkers, but the effect on insulin sensitivity is controversial. We investigated the effects of 2 doses of pravastatin (40 and 10 mg/day) on insulin sensitivity and serum inflammatory markers in nondiabetic hypercholesterolemic patients. Methods: This was a randomized, parallel, comparative design study. A total of 40 nondiabetic subjects with elevated low-density lipoprotein (LDL) cholesterol were randomized to either the 40 mg pravastatin/day group (n =21) or the 10 mg pravastatin/day group (n=19) for 8 weeks. The fasting serum lipid profile, homeostasis model assessment (HOMA), glucose and insulin response of the two-hour glucose tolerance test (2 h-OGTT), and several inflammatory markers were determined. Results: Eight weeks of pravastatin treatment in both dose groups led to a significant reduction in serum LDL cholesterol, total cholesterol, triglycerides, and total cholesterol/high-density lipoprotein (HDL) cholesterol ratios (all p<0.01 in 40 mg group and all p<0.05 in 10 mg group), though the 40 mg group had greater effects. Although the fasting HOMA insulin resistance did not change significantly in either group, glucose and insulin areas under the curve of 2 h-OGTT were significantly decreased, suggesting improvement in insulin sensitivity post glucose challenge. Serum CD-40 ligand concentration was significantly reduced in the 40 mg pravastatin/day group and soluble P-selectin significantly reduced in both groups. Conclusions: Pravastatin treatment, at 10 mg or 40 mg daily for 8 weeks, reduced serum lipids and some inflammatory markers in nondiabetic hypercholesterolemic subjects. Furthermore, insulin resistance was improved even in short-teen treatment by pravastatin. (C) 2008 Elsevier B.V. All rights reserved