A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation, yet these can be time consuming and do not provide integrated visual aids for data interpretation. We, therefore, develop FUMA: an integrative web-based platform using information from multiple biological resources to facilitate functional annotation of GWAS results, gene prioritization and interactive visualization. FUMA accommodates positional, expression quantitative trait loci (eQTL) and chromatin interaction mappings, and provides gene-based, pathway and tissue enrichment results. FUMA results directly aid in generating hypotheses that are testable in functional experiments aimed at proving causal relations.

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Functional mapping and annotation of genetic associations with FUMA

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

/pdf/genetic-meta-analysis-of-diagnosed-alzheimer-s-disease-4jgud8f7lh.pdf

Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Historically women have been attended and supported by other women during labour and birth However in many countries, as more women are giving birth in hospital rather than at home, continuous support during labour has become the exception rather than the norm This may contribute to the dehumanisation of women's childbirth experiences Modern obstetric care frequently subjects women to institutional routines, which may have adverse effects on the progress of labour Supportive care during labour may involve emotional support, comfort measures, information and advocacy These may enhance physiologic labour processes as well as women's feelings of control and competence, and thus reduce the need for obstetric intervention The review of studies included 23 trials (22 providing data), from 16 countries, involving more than 15,000 women in a wide range of settings and circumstances The continuous support was provided either by hospital staff (such as nurses or midwives), women who were not hospital employees and had no personal relationship to the labouring woman (such as doulas or women who were provided with a modest amount of guidance), or by companions of the woman's choice from her social network (such as her husband, partner, mother, or friend) Women who received continuous labour support were more likely to give birth 'spontaneously', ie give birth with neither caesarean nor vacuum nor forceps In addition, women were less likely to use pain medications, were more likely to be satisfied, and had slightly shorter labours Their babies were less likely to have low five-minute Apgar scores No adverse effects were identified We conclude that all women should have continuous support during labour Continuous support from a person who is present solely to provide support, is not a member of the woman's social network, is experienced in providing labour support, and has at least a modest amount of training, appears to be most beneficial In comparison with having no companion during labour, support from a chosen family member or friend appears to increase women's satisfaction with their childbearing experience

Continuous support for women during childbirth.

https://spiral.imperial.ac.uk/bitstream/10044/1/53407/11/1-s2.0-S1053811917308613-main.pdf

Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.

Biobank-based genome-wide association studies are enabling exciting insights in complex trait genetics, but much uncertainty remains over best practices for optimizing statistical power and computational efficiency in GWAS while controlling confounders. Here, we introduce a much faster version of our BOLT-LMM Bayesian mixed model association method—capable of running analyses of the full UK Biobank cohort in a few days on a single compute node—and show that it produces highly powered, robust test statistics when run on all 459K European samples (retaining related individuals). When used to conduct a GWAS for height in UK Biobank, BOLT-LMM achieved power equivalent to linear regression on 650K samples—a 93% increase in effective sample size versus the common practice of analyzing unrelated British samples using linear regression (UK Biobank documentation; Bycroft et al. bioRxiv). Across a broader set of 23 highly heritable traits, the total number of independent GWAS loci detected increased from 5,839 to 10,759, an 84% increase. We recommend the use of BOLT-LMM (retaining related individuals) for biobank-scale analyses, and we have publicly released BOLT-LMM summary association statistics for the 23 traits analyzed as a resource for all researchers.

/pdf/mixed-model-association-for-biobank-scale-datasets-4bhk4z53vb.pdf

Mixed-model association for biobank-scale datasets.

BACKGROUND: Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS: This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

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Stephanie Karpoff

Papers

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis