Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates

BACKGROUND: Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Twin and family studies point to a significant genetic etiology, and several groups have performed genomic linkage screens to identify susceptibility loci. METHODS: We performed a genome-wide linkage screen in 158 combined Tufts, Vanderbilt and AGRE (Autism Genetics Research Exchange) multiplex autism families using parametric and nonparametric methods with a categorical autism diagnosis to identify loci of main effect. Hypothesizing interdependence of genetic risk factors prompted us to perform exploratory studies applying the Ordered-Subset Analysis (OSA) approach using LOD scores as the trait covariate for ranking families. We employed OSA to test for interlocus correlations between loci with LOD scores ≥1.5, and empirically determined significance of linkage in optimal OSA subsets using permutation testing. Exploring phenotypic correlates as the basis for linkage increases involved comparison of mean scores for quantitative trait-based subsets of autism between optimal subsets and the remaining families. RESULTS: A genome-wide screen for autism loci identified the best evidence for linkage to 17q11.2 and 19p13, with maximum multipoint heterogeneity LOD scores of 2.9 and 2.6, respectively. Suggestive linkage (LOD scores ≥1.5) at other loci included 3p, 6q, 7q, 12p, and 16p. OSA revealed positive correlations of linkage between the 19p locus and 17q, between 19p and 6q, and between 7q and 5p. While potential phenotypic correlates for these findings were not identified for the chromosome 7/5 combination, differences indicating more rapid achievement of "developmental milestones" was apparent in the chromosome 19 OSA-defined subsets for 17q and 6q. OSA was used to test the hypothesis that 19p linkage involved more rapid achievement of these milestones and it revealed significantly increased LOD* scores at 19p13. CONCLUSIONS: Our results further support 19p13 as harboring an autism susceptibility locus, confirm other linkage findings at 17q11.2, and demonstrate the need to analyze more discreet trait-based subsets of complex phenotypes to improve ability to detect genetic effects

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 GWAS 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-value OBFC1indicated 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 our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

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 < 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

Prenatal exercise (including but not limited to pelvic floor muscle training) and urinary incontinence during and following pregnancy: a systematic review and meta-analysis

Objective To examine the relationships between prenatal physical activity and prenatal and postnatal urinary incontinence (UI). Design Systematic review with random effects meta-analysis and meta-regression. Data sources Online databases were searched up to 6 January 2017. Study eligibility criteria Studies of all designs were included (except case studies) if they were published in English, Spanish or French and contained information on the Population (pregnant women without contraindication to exercise), Intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone [ exercise-only ] or in combination with other intervention components [e.g., dietary; exercise + co-intervention]), Comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and Outcome (prenatal or postnatal UI). Results 24 studies (n=15982 women) were included. Low\u27 to moderate\u27 quality evidence revealed prenatal pelvic floor muscle training (PFMT) with or without aerobic exercise decreased the odds of UI in pregnancy (15 randomised controlled trials (RCTs), n=2764 women; OR 0.50, 95% CI 0.37 to 0.68, I-2=60%) and in the postpartum period (10 RCTs, n=1682 women; OR 0.63, 95%CI 0.51, 0.79, I-2=0%). When we analysed the data by whether women were continent or incontinent prior to the intervention, exercise was beneficial at preventing the development of UI in women with continence, but not effective in treating UI in women with incontinence. There was low\u27 quality evidence that prenatal exercise had a moderate effect in the reduction of UI symptom severity during (five RCTs, standard mean difference (SMD) -0.54, 95%CI -0.88 to -0.20, I-2=64%) and following pregnancy (three RCTs, moderate\u27 quality evidence; SMD -0.54, 95% CI -0.87 to -0.22, I-2=24%). Conclusion Prenatal exercise including PFMT reduced the odds and symptom severity of prenatal and postnatal UI. This was the case for women who were continent before the intervention. Among women who were incontinent during pregnancy, exercise training was not therapeutic

Impact of prenatal exercise on maternal harms, labour and delivery outcomes: a systematic review and meta-analysis

Objective To perform a systematic review of the relationships between prenatal exercise and maternal harms including labour/delivery outcomes. Design Systematic review with random effects meta-analysis and meta-regression. Datasources Online databases were searched up to 6 January 2017. Study eligibility criteria Studies of all designs were included (except case studies) if they were published in English, Spanish or French and contained information on the population (pregnant women without contraindication to exercise), intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise), comparator (no exercise or different frequency, intensity, duration, volume and type of exercise, alone [ exercise-only ] or in combination with other intervention components [e.g., dietary; exercise + co-intervention ]) and outcome (preterm/prelabour rupture of membranes, caesarean section, instrumental delivery, induction of labour, length of labour, vaginal tears, fatigue, injury, musculoskeletal trauma, maternal harms (author defined) and diastasis recti). Results 113 studies (n=52 858 women) were included. \u27Moderate\u27 quality evidence from exercise-only randomised controlled trials (RCTs) indicated a 24% reduction in the odds of instrumental delivery in women who exercised compared with women who did not (20 RCTs, n=3819; OR 0.76, 95% CI 0.63 to 0.92, I (2)= 0 %). The remaining outcomes were not associated with exercise. Results from meta-regression did not identify a dose-response relationship between frequency, intensity, duration or volume of exercise and labour and delivery outcomes. Summary/conclusions Prenatal exercise reduced the odds of instrumental delivery in the general obstetrical population. There was no relationship between prenatal exercise and preterm/prelabour rupture of membranes, caesarean section, induction of labour, length of labour, vaginal tears, fatigue, injury, musculoskeletal trauma, maternal harms and diastasis recti

In Situ Enhancement and Isotopic Labeling of Biogenic Coalbed Methane

Subsurface microbial (biogenic) methane production is an important part of the global carbon cycle that has resulted in natural gas accumulations in many coal beds worldwide. Laboratory studies suggest that complex carbon-containing nutrients (e.g., yeast or algae extract) can stimulate methane production, yet the effectiveness of these nutrients within coal beds is unknown. Here, we use downhole monitoring methods in combination with deuterated water (D2O) and a 200-liter injection of 0.1% yeast extract (YE) to stimulate and isotopically label newly generated methane. A total dissolved gas pressure sensor enabled real-time gas measurements (641 days preinjection and for 478 days postinjection). Downhole samples, collected with subsurface environmental samplers, indicate that methane increased 132% above preinjection levels based on isotopic labeling from D2O, 108% based on pressure readings, and 183% based on methane measurements 266 days postinjection. Demonstrating that YE enhances biogenic coalbed methane production in situ using multiple novel measurement methods has immediate implications for other field-scale biogenic methane investigations, including in situ methods to detect and track microbial activities related to the methanogenic turnover of recalcitrant carbon in the subsurface