Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.

Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine-mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggests generalizability of genetic mechanisms underpinning obesity-related traits across populations.

Sex-specific associations between adipokine profiles and carotid-intima media thickness in the Cameron County Hispanic Cohort (CCHC).

BACKGROUND: Adipokines are hormones secreted from adipose tissue and are associated with cardiometabolic diseases (CMD). Functional differences between adipokines (leptin, adiponectin, and resistin) are known, but inconsistently reported associations with CMD and lack of studies in Hispanic populations are research gaps. We investigated the relationship between subclinical atherosclerosis and multiple adipokine measures. METHODS: Cross-sectional data from the Cameron County Hispanic Cohort (N = 624; mean age = 50; Female = 70.8%) were utilized to assess associations between adipokines [continuous measures of adiponectin, leptin, resistin, leptin-to-adiponectin ratio (LAR), and adiponectin-resistin index (ARI)] and early atherosclerosis [carotid-intima media thickness (cIMT)]. We adjusted for sex, age, body mass index (BMI), smoking status, cytokines, fasting blood glucose levels, blood pressure, lipid levels, and medication usage in the fully adjusted linear regression model. We conducted sexes-combined and sex-stratified analyses to account for sex-specificity and additionally tested whether stratification of participants by their metabolic status (metabolically elevated risk for CMD as defined by having two or more of the following conditions: hypertension, dyslipidemia, insulin resistance, and inflammation vs. not) influenced the relationship between adipokines and cIMT. RESULTS: In the fully adjusted analyses, adiponectin, leptin, and LAR displayed significant interaction by sex (p < 0.1). Male-specific associations were between cIMT and LAR [ß(SE) = 0.060 (0.016), p = 2.52 × 10-4], and female-specific associations were between cIMT and adiponectin [ß(SE) = 0.010 (0.005), p = 0.043] and ARI [ß(SE) = - 0.011 (0.005), p = 0.036]. When stratified by metabolic health status, the male-specific positive association between LAR and cIMT was more evident among the metabolically healthy group [ß(SE) = 0.127 (0.015), p = 4.70 × 10-10] (p for interaction by metabolic health < 0.1). However, the female-specific associations between adiponectin and cIMT and ARI and cIMT were observed only among the metabolically elevated risk group [ß(SE) = 0.014 (0.005), p = 0.012 for adiponectin; ß(SE) = - 0.015 (0.006), p = 0.013 for ARI; p for interaction by metabolic health < 0.1]. CONCLUSION: Associations between adipokines and cIMT were sex-specific, and metabolic health status influenced the relationships between adipokines and cIMT. These heterogeneities by sex and metabolic health affirm the complex relationships between adipokines and atherosclerosis.

Genetic pleiotropy underpinning adiposity and inflammation in self-identified Hispanic/Latino populations.

BACKGROUND: Concurrent variation in adiposity and inflammation suggests potential shared functional pathways and pleiotropic disease underpinning. Yet, exploration of pleiotropy in the context of adiposity-inflammation has been scarce, and none has included self-identified Hispanic/Latino populations. Given the high level of ancestral diversity in Hispanic American population, genetic studies may reveal variants that are infrequent/monomorphic in more homogeneous populations. METHODS: Using multi-trait Adaptive Sum of Powered Score (aSPU) method, we examined individual and shared genetic effects underlying inflammatory (CRP) and adiposity-related traits (Body Mass Index [BMI]), and central adiposity (Waist to Hip Ratio [WHR]) in HLA participating in the Population Architecture Using Genomics and Epidemiology (PAGE) cohort (N = 35,871) with replication of effects in the Cameron County Hispanic Cohort (CCHC) which consists of Mexican American individuals. RESULTS: Of the > 16 million SNPs tested, variants representing 7 independent loci were found to illustrate significant association with multiple traits. Two out of 7 variants were replicated at statistically significant level in multi-trait analyses in CCHC. The lead variant on APOE (rs439401) and rs11208712 were found to harbor multi-trait associations with adiposity and inflammation. CONCLUSIONS: Results from this study demonstrate the importance of considering pleiotropy for improving our understanding of the etiology of the various metabolic pathways that regulate cardiovascular disease development.

The association between alcohol intake and fecundability during menstrual cycle phases.

STUDY QUESTION: Is increased alcohol intake in different phases of the menstrual cycle associated with fecundability in women? SUMMARY ANSWER: Heavy intake (>6 drinks/week) of alcoholic beverages in the luteal phase and ovulatory subphase was associated with reduced odds of conception; moderate intake (3-6 drinks/week) during the luteal phase was also associated with reduced fecundability. WHAT IS KNOWN ALREADY: Despite strong indications for increased risk of infertility among drinking women with intention to conceive, inconsistencies in previous results point to possible residual confounding, and have not thoroughly investigated timing of drinking and other drinking patterns during the menstrual cycle. STUDY DESIGN, SIZE, DURATION: Participants in The Mount Sinai Study of Women Office Workers (MSSWOW), a prospective cohort study of fertility, were recruited and followed between 1990 and 1994, and completed daily diaries reporting their alcohol intake (type and number of drinks) for a maximum of 19 months of follow-up (N = 413). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were between 19 and 41 years of age. After completion of baseline surveys, they were asked to record their alcoholic beverage intake as number of drinks of beer, wine, and liquor per day, in addition to other exposures such as caffeine and smoking. Furthermore, they submitted urine samples each month to assess pregnancy. Menstrual cycle phases were calculated using the Knaus-Ognio approach. Discrete survival analysis methods were employed to estimate the association between categories of alcohol intake in each phase of menstrual cycle and fecundability. MAIN RESULTS AND THE ROLE OF CHANCE: In the luteal phase, both moderate drinking (3-6 drinks/week, Fecundability Odds Ratio (FOR)=0.56, CI: 0.31, 0.98) and heavy drinking (>6 drinks/week, FOR = 0.51, CI: 0.29, 0.89) were associated with a reduction in fecundability, compared to non-drinkers. For the follicular phase, heavy drinking in the ovulatory sub-phase (FOR = 0.39, CI: 0.19, 0.72) was similarly associated with reduced fecundability, compared to non-drinkers. For the pre-ovulatory sub-phase, heavy drinking (>6 drinks/week, FOR = 0.54, CI: 0.29, 0.97) was associated with reduction in fecundability, but this association was inconsistent when subjected to sensitivity tests. Each extra day of binge drinking was associated with 19% (FOR = 0.81, CI: 0.63, 0.98), and 41% (FOR = 0.59, CI: 0.33, 0.93) reduction in fecundability for the luteal phase and ovulatory sub-phase respectively, but no association was observed in the pre-ovulatory sub-phase. No meaningful differences in fecundability between beverages were observed in any menstrual phase. LIMITATIONS, REASONS FOR CAUTION: Patterns of alcohol intake in this cohort suggest a lower average alcohol intake compared to more recent national averages for the same demographic group. Sample sizes were small for some subgroups, resulting in limited power to examine specific beverage types in different phases of the menstrual cycle, or to assess interaction. In addition, the influence of male partner alcohol intake was not assessed, the data relied on self-report, and residual confounding (e.g. unmeasured behaviors correlated with alcohol intake) is a possibility. WIDER IMPLICATIONS OF THE FINDINGS: Results suggest an inverse association between alcohol and fecundability, and support the relevance of menstrual cycle phases in this link. More specifically, moderate to heavy drinking during the luteal phase, and heavy drinking in the ovulatory window, could disturb the delicate sequence of hormonal events, affecting chances of a successful conception. STUDY FUNDING/COMPETING INTEREST(S): Authors declare no conflict of interest. This work was supported by the National Institutes of Health grant, R01-HD24618. TRIAL REGISTRATION NUMBER: N/A.