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Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

Background: Use of calcium channel blockers (CCBs) has been associated with increased risk of breast cancer in some, but not all, studies. Differences in reported associations from prior studies may be due, in part, to inadequate control of confounding factors.Methods: Participants were 28,561 postmenopausal women from the Women's Health Initiative who reported use of either CCBs or other antihypertensive medications (AHMs) at baseline; 1,402 incident breast cancer cases were diagnosed during 12 years of follow-up. Adjusted Cox regression models were used to estimate HRs and 95% confidence intervals (CI) for the associations between CCB use relative to other AHM use and breast cancer risk.Results: Use of CCBs was not associated with breast cancer risk (HR, 1.06; 95% CI, 0.94-1.20) relative to use of other AHMs. Associations approximated the null value when CCBs were considered by duration of use, length of action, or drug class.Conclusions: We provide additional evidence that CCBs do not influence breast cancer risk in postmenopausal women.Impact: The results from this study, which includes strong control for potential confounding factors, cast doubt on increases in risk with CCBs. Cancer Epidemiol Biomarkers Prev; 26(8); 1345-8. ©2017 AACR.

Neuritin, also known as candidate plasticity gene 15 (CPG15), was first identified as one of the activity‐dependent gene products in the brain. Previous studies have been reported that Neuritin induces neuritogenesis, neurite arborization, neurite outgrowth and synapse formation, which are involved in the development and functions of the central nervous system. However, the role of Neuritin in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of Neuritin steering Schwann cell dedifferentiation during Wallerian degeneration (WD) in injured peripheral nerve. Herein, using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that Neuritin vividly accelerates Schwann cell dedifferentiation. Moreover, we found that Neuritin promotes Schwann cell demyelination as well as axonal degeneration, phagocytosis, secretion capacity. In summary, we first described Neuritin acts as a positive regulator for Schwann cell dedifferentiation and WD after peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

ObjectiveTelomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality among AfAm.Approach and resultsUsing a case-cohort design, 1525 postmenopausal women (667 AfAm and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas AfAm experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in AfAm. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in AfAm.ConclusionsAs one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and AfAm postmenopausal women.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites in some studies; however, we recently reported no association between their use and total cancer risk in women in a prospective study. Here we examine the association between NSAIDs and total and site-specific cancer incidence in the large, prospective Women's Health Initiative (WHI). Women (129,013) were recruited to participate in the WHI at 40 US clinical centers from 1993 to 1998 and followed prospectively. After 9.7 years of follow-up, 12,998 incident, first primary, invasive cancers were diagnosed. NSAID use was systematically collected at study visits. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs use and total and site-specific cancer risk. Relative to non-use, consistent use (i.e., use at baseline and year 3 of follow-up) of any NSAID was not associated with total cancer risk (HR 1.00, 95% CI: 0.94-1.06). Results for individual NSAIDs were similar to the aggregate measure. In site-specific analyses, NSAIDs were associated with reduced risks of colorectal cancer, ovarian cancer, and melanoma. Our study confirms a chemopreventive benefit for colorectal cancer in women and gives preliminary evidence for a reduction of the risk of some rarer cancers. NSAIDs' benefit on cancer risk was therefore limited to specific sites and not evident when total cancer risk was examined. This information may be of importance when NSAIDs are considered as chemopreventive agents.

BackgroundThe purpose of this study was to describe the longitudinal trajectories and bidirectional relationships of the physical-social and emotional functioning (EF) dimensions of positive aging and to identify their baseline characteristics.MethodsWomen age 65 and older who enrolled in one or more Women's Health Initiative clinical trials (WHI CTs) and who had positive aging indicators measured at baseline and years 1, 3, 6, and 9 were included in these analyses (N = 2281). Analytic strategies included latent class growth modeling to identify longitudinal trajectories and multinomial logistic regression to examine the effects of baseline predictors on these trajectories.ResultsA five-trajectory model was chosen to best represent the data. For Physical-Social Functioning (PSF), trajectory groups included Low Maintainer (8.3%), Mid-Low Improver (10.4%), Medium Decliner (10.7%), Mid-High Maintainer (31.2%), and High Maintainer (39.4%); for EF, trajectories included Low Maintainer (3%), Mid-Low Improver (9%), Medium Decliner (7.7%), Mid-High Maintainer (22.8%), and High Maintainer (57.5%). Cross-classification of the groups of trajectories demonstrated that the impact of a high and stable EF on PSF might be greater than the reverse. Low depression symptoms, low pain, and high social support were the most consistent predictors of high EF trajectories.ConclusionAging women are heterogeneous in terms of positive aging indicators for up to 9 years of follow-up. Interventions aimed at promoting sustainable EF might have diffused effects on other domains of healthy aging.

BackgroundAlthough epidemiologic studies have shown associations between sedentary behavior and mortality, few have focused on older women with adequate minority representation and few have controlled for both physical activity and functional status.PurposeThe objective of this study was to determine the relationship between sedentary time and total; cardiovascular disease (CVD); coronary heart disease (CHD); and cancer mortality in a prospective, multiethnic cohort of postmenopausal women.MethodsThe study population included 92,234 women aged 50-79 years at baseline (1993-1998) who participated in the Women's Health Initiative Observational Study through September 2010. Self-reported sedentary time was assessed by questionnaire and examined in 4 categories (≤4, >4-8, ≥8-11, >11 hours). Mortality risks were examined using Cox proportional hazard models adjusting for confounders. Models were also stratified by age, race/ethnicity, body mass index, physical activity, physical function, and chronic disease to examine possible effect modification. Analyses were conducted in 2012-2013.ResultsThe mean follow-up period was 12 years. Compared with women who reported the least sedentary time, women reporting the highest sedentary time had increased risk of all-cause mortality in the multivariate model (HR=1.12, 95% CI=1.05, 1.21). Results comparing the highest versus lowest categories for CVD, CHD, and cancer mortality were as follows: HR=1.13, 95% CI=0.99, 1.29; HR=1.27, 95% CI=1.04, 1.55; and HR=1.21, 95% CI=1.07, 1.37, respectively. For all mortality outcomes, there were significant linear tests for trend.ConclusionsThere was a linear relationship between greater amounts of sedentary time and mortality risk after controlling for multiple potential confounders.

BackgroundTo develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living.MethodsData from Women's Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services).ResultsWe identified a multidimensional phenotype of positive aging that included two factors: Physical-Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical-Social Functioning was the strongest predictor. Each standard deviation of increase in Physical-Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living.ConclusionsPhysical-Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Sedentary behavior is associated with deleterious health outcomes. This study evaluated the association between sedentary time and physical function among postmenopausal women in the Women's Health Initiative Observational Study. Data for this prospective cohort study were collected between 1993-1998 (enrollment) and 2009, with an average of 12.3 follow-up years. Analyses included 61,609 women (aged 50-79 years at baseline). Sedentary time was estimated by questionnaire; physical function was measured using the RAND SF-36 physical function scale. Mixed-model analysis of repeated measures was used to estimate the relationship of sedentary time exposures and changes in physical function adjusting for relevant covariates. Compared to women reporting sedentary time of ≤6 hours/day, those with greater amounts of sedentary time (>6-8 hours/day, >8-11 hours/day, >11 hours/day) reported lower physical function between baseline and follow up (coefficient = -0.78, CI = -0.98, -0.57, -1.48, CI = -1.71, -1.25, -3.13, and CI = -3.36, -2.89, respectively P < 0.001). Sedentary time was strongly associated with diminished physical function and most pronounced among older women and those reporting the greatest sedentary time. Maintaining physical function with age may be improved by pairing messages to limit sedentary activities with those promoting recommended levels of physical activity.

This work introduces a new permutation-symmetry-adapted machine learning diabatization procedure, termed the diabatization by equivariant neural network (DENN). In this approach, the permutation symmetric and anti-symmetric elements in diabatic potential energy metrics (DPEMs) were simultaneously simulated by the equivariant neural network. The diabatization by deep neural network scheme was adopted for machine learning diabatization, and non-zero diabatic coupling was included to increase accuracy in the near degenerate region. Based on DENN, the global DPEMs for 11A′ and 21A′ states of MgH2 have been constructed. To the best of our knowledge, these are the first global DPEMs for the MgH2 system. The root-mean-square-errors (RMSEs) for diagonal elements (H11 and H22) and the off-diagonal element (H12) around the conical intersection region were 5.824, 5.307, and 5.796 meV, respectively. The RMSEs of global adiabatic energies for two adiabatic states were 4.613 and 12.755 meV, respectively. The spectroscopic calculations of the 11A′ state in the linear HMgH region are in good agreement with the experiment and previous theoretical results. The differences between calculated frequencies and corresponding experiment values are 1.38 and 1.08 cm−1 for anti-symmetric stretching fundamental vibrational frequency and first overtone. The global DPEMs obtained in this work should be useful for further quantum mechanics dynamic simulations on the MgH2 system. [ABSTRACT FROM AUTHOR]