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Introduction: The Hispanic/Latino population experiences extensive socioeconomic adversity across the lifespan. Yet little is known about the role of lifecourse socioeconomic position (SEP) on cardiovascular health (CVH) in this population. Hypothesis: Childhood and adulthood SEP as well as socioeconomic mobility are associated with changes in CVH over time in Hispanic/Latino adults. Methods: We used longitudinal data (N = 14,604) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based cohort study conducted in four major U.S cities. We determined childhood SEP using participant-reported parental education classified as No schooling; Elementary, middle, or high school; and more than high school (HS). Adulthood SEP was determined through an index with a score ranging from 0 to 9 combining participants’ education, occupation, annual household income, and assets, and classified as low (0), middle (1-4), and high SEP (5-9). Using childhood and adulthood SEP, we classified participants into socioeconomic mobility categories (e.g., persisting low, downward, or upward mobility, etc.). Using the four-health metrics of the American Heart Association “Life’s Essential 8” (i.e., body mass index, non-HDL cholesterol, fasting blood glucose or HbA1c, and blood pressure) we built a score of ideal CVH ranging from 0 to 100. CVH was assessed at baseline and at the 6-year follow-up. Since changes in CVH over time differed by CVH at baseline, we conducted linear mixed effects models stratifying by CVH at baseline, with random intercept and slope, adjusting for age, sex, Hispanic/Latino background, study center, U.S or foreign-born, years in the U.S, as well as baseline health insurance, diet, physical activity, hours of sleep per night, smoking, alcohol consumption, and antihypertensive and cholesterol medication use. Results: 8% of parents did not have any formal education, 11% of the population had low SEP in adulthood, and 37% showed upward socioeconomic mobility. Among those with low (CVH score HS: 0.24, 95% CI: 0.00, 0.47). There was no longitudinal association among those with low baseline CVH. High adulthood SEP was associated with greater CVH at baseline for those with low (Coefficient: 2.55 95% CI: 1.25, 3.85) and moderate to high CVH (Coefficient: 1.36 95% CI: 0.09, 2.62). However, it was not associated with changes in CVH. Socioeconomic mobility was associated with greater baseline CVH as well as with improvements in CVH over time. Conclusion: Among Hispanic/Latino population with high initial CVH, high childhood SEP and socioeconomic mobility were associated with better CVH over time.

Purpose Childhood adversity is associated with increased risk of adult disease, including type II diabetes and hypertension. However, little is known about potential associations between childhood adversity and adverse pregnancy outcomes. The goal of this study was to examine the relationship between adverse childhood experiences (ACEs) and ever experiencing gestational diabetes mellitus (GDM) or a hypertensive disorder of pregnancy (HDP) in a cohort of Hispanic or Latina women. Methods We analyzed data from 2319 women from the Hispanic Community Health Study/Study of Latinos who had ever given birth to a liveborn infant. We fit separate logistic regression models accounting for sample weights to examine the association between ACEs and risk of GDM and HDP adjusting for Hispanic/Latino background, age at immigration to the United States, and education. Results Women who reported four or more ACEs did not show increased odds of GDM or HDP compared with those who reported three or fewer (GDM adjusted odds ratio: 0.8 [0.5, 1.3]; HDP adjusted OR: 1.0 [0.7, 1.5]). Conclusions Unlike previous research with majority non-Hispanic White cohorts, there was no association between ACEs and GDM or HDP. Future research should explore if this relationship varies by race/ethnicity in multiethnic cohorts.

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.

Background United States (US) Hispanic/Latinos experience a disproportionate burden of obesity, which may in part be related to demographic or sociocultural factors, including acculturation to an US diet or inactive lifestyle. Therefore, we sought to describe the association between adulthood weight histories and demographic and sociocultural factors in a large diverse community-based cohort of US Hispanic/Latinos. Methods We estimated the effect of several factors on weight gain across adulthood, using multivariable linear mixed models to leverage 38,759 self-reported current body weights and weight histories recalled for 21, 45 and 65 years of age, from 15,203 adults at least 21 years of age at the baseline visit of the Hispanic Community Health Study/Study of Latinos (2008–2011). Results The average rate of weight gain was nearly 10 kg per decade in early adulthood, but slowed to Conclusions Using self-reported and weight history data in a diverse sample of US Hispanic/Latinos, we revealed that both demographic and sociocultural factors were associated with the patterning of adulthood weight gain in this sample. Given the steep rate of weight gain in this population and the fact that many Hispanic/Latinos living in the US immigrated as adults, efforts to promote weight maintenance across the life course, including after immigration, should be a top priority for promoting Hispanic/Latino health and addressing US health disparities more broadly.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Purpose United States (US) Latinos have the lowest educational attainment of any US racial/ethnic group, which may contribute to their disparate burden of Type 2 Diabetes. Herein, we aimed to examine the association between intergenerational educational mobility and Type 2 Diabetes among US Latino adults. Methods We used data from the Ninos Lifestyle and Diabetes Study (2013–2014) and the Sacramento Area Latino Study on Aging (1998–1999) to link 616 adult Latino children to their parents. Model-based standardization and robust Poisson regression were used to estimate the prevalence of prediabetes, Type 2 Diabetes, treatment and glycemic control, and describe their associations with intergenerational educational mobility. Results Adult children with stable high intergenerational educational attainment had a higher prevalence of prediabetes (Prevalence Ratio, PR=1.58; 95% Confidence Interval, CI=1.08, 2.34) and lower prevalence of Type 2 Diabetes (PR=0.64, CI=0.41, 0.99), as compared to those who experienced low educational attainment across generations. Downward mobility was associated with a higher prevalence of prediabetes (PR=1.54, CI=1.06, 2.23) and worse glycemic control (PR=2.20, CI=1.13, 4.30), and upward mobility was associated with a lower prevalence of Type 2 Diabetes (PR=0.39, CI=0.22, 0.70). Conclusions Our findings from a predominantly Mexican-heritage community suggest that higher education across generations may buffer individuals from glycemic dysregulation. As such, higher education may be a promising public health target to address the rising burden of Type 2 Diabetes in the US.

OBJECTIVE This study aimed to estimate the association between cycles of poverty, measured by intergenerational educational attainment (IEA), and the burden of obesity and metabolic dysfunction among Hispanic/Latino individuals in the United States. METHODS This is a cross-sectional study utilizing data from 392 adults linked to 286 biologic parents from the Ninos Lifestyle and Diabetes Study and the Sacramento Area Latino Study on Aging. The educational attainment of parents and offspring was dichotomized in order to categorize IEA. Outcomes included obesity and metabolic syndrome (MetS). Model-based standardization with population weights was used to compare obesity and MetS across generations, and Poisson regression was used to estimate prevalence ratios by IEA. RESULTS A higher prevalence of obesity and MetS was observed in offspring (54% and 69%, respectively) compared with their parents (48% and 42%, respectively). Compared with stable-low IEA, any category with high offspring education was associated with lower obesity and MetS prevalence. The upwardly mobile group saw the greatest benefit; they were 38% (95% CI: 10%-57%) and 46% (95% CI: 21%-63%) less likely to have obesity or MetS. CONCLUSIONS IEA strongly patterns cardiometabolic health among Hispanic/Latino individuals living in the United States, suggesting that promotion of higher education is associated with reductions in obesity and MetS, potentially benefitting future generations of this population.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance—representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Background: DNA methylation (DNAm)-based measures of aging, termed epigenetic clocks (EC), are associated with aging-related outcomes including cardiovascular disease (CVD) and all-cause mortality. Associations of ECs with heart failure (HF) are unclear. We tested whether ECs were positively associated with risk of incident HF in the Atherosclerosis Risk in Communities (ARIC) study and evaluated whether adding ECs to Pooled Cohort Equation (PCE) variables improved risk prediction. Methods: We measured DNAm in peripheral blood leukocytes in 2,263 African American (mean age=56.3 years) and 925 European American (mean age=59.5 years) participants using the Illumina HM450K and calculated 7 ECs: Horvath, Hannum, extrinsic (EEAA) and intrinsic (IEAA) epigenetic age acceleration, Hannum, PhenoAge, and GrimAge. HF was ascertained by ICD- 9 code 428 and adjudication by an expert panel. We carried out race stratified proportional hazards regression to test associations ECs with incident HF, adjusting for PCE variables: age, sex, smoking, total cholesterol, HDL, systolic blood pressure (SBP), antihypertensive medication use, and diabetes. We calculated area under the curve (AUC) and integrated discrimination index (IDI) to evaluate improvement in risk prediction when adding the ECs to PCE variables. Results: The number of incident HF events and mean follow-up time in African Americans and European Americans were 640 (189 in the first 10 years) and 19.3 years, and 191 and 21.7 years, respectively. All 7 ECs were positively associated with HF in both African Americans and European Americans. In African Americans with follow-up restricted to the first 10 years, the HR for a one SD increment in GrimAge (5.64 years) was 1.57 (95% CI=1.31, 1.88), comparable to that for a one-SD (5.82 years) increment in age (HR=1.58, 95% CI=1.36, 1.83) and greater than that for a one-SD (20.2mmHg) increment in SBP (HR=1.33, 95% CI=1.18, 1.51). In European Americans across the entire follow-up period, the HR for a one-SD increment in GrimAge (6.13 years) was 1.22 (95% CI=1.06, 1.41), smaller than that for a one-SD (5.50 years) increment in age (HR=1.93, 95% CI=1.63, 2.29) and larger than that for a one-SD (17.9 mmHG) increment in SBP (HR=1.13, 95% CI=0.98, 1.30). In African Americans with follow-up restricted to the first 10 years, adding GrimAge to PCE variables increased AUC by 0.019 (95% CI=0.003, 0.035) and the IDI was 0.010 (95% CI=0.002, 0.019). In European Americans, adding GrimAge did not change AUC appreciably (0.004, 95% CI=-0.006, 0.014) and the IDI was 0.002 (95% CI=0.000, 0.005). Conclusion: ECs are positively associated with HF in African American and European American participants independent of traditional CVD risk factors. GrimAge modestly improved heart failure risk prediction in African Americans. HF-specific DNAm-based measures should be developed and evaluated for improvement in risk prediction.

Introduction: Polycystic Ovary Syndrome (PCOS) is associated with increased Metabolic Syndrome (MetS), however, these findings have not been characterized in Hispanic/Latina women who are disproportionately burdened by obesity and cardiovascular disease risk compared to non-Hispanic whites. It is also unclear if this association is moderated by elevated high-sensitivity C-Reactive Protein (hs-CRP) levels, a marker for inflammation and a predictor of cardiovascular disease. Hypothesis: In Hispanic/Latina women, we hypothesized that 1) PCOS (self-reported diagnosis and signs) is associated with a higher prevalence of MetS compared to those not reporting PCOS 2) elevated hs-CRP is associated with MetS, and 3) the PCOS-MetS association is moderated by elevated hs-CRP. Methods: We used information from reproductive and economic questionnaires and venous blood measurements collected in Hispanic Community Health Study/Study of Latinos (2008-2017), a U.S. community-based cohort study of Hispanic/Latino adults. PCOS was operationalized as either 1) signs of PCOS (e.g., menstrual cycles >35 days, irregular cycles (at age 20 to 40 years old when not using birth control pills or other hormone medications and not pregnant or breastfeeding) or 2) having answered “yes” to a self-reported question on PCOS. MetS was operationalized as ≥3 elevated subcomponents of MetS (i.e., waist circumference, hypertension, insulin resistance, lipid profile, and triglycerides). A hs-CRP value ≥3.0 mg/L was considered elevated. We adjusted for the complex survey study design, age, study center, Hispanic/Latina background, and age at immigration in all models. Results: The overall (unweighted N=9582) age ranged from 18 to 76 years (mean=41.74, SD=14.18). The prevalence of PCOS (self-reported diagnosis and signs) was 12% (1008/7366), prevalence of MetS was 40% (2380/3495), prevalence of elevated-hsCRP was 44% (3704/4667). PCOS was associated with a significantly higher odds of MetS before (OR 1.35, 95% CI: 1.06-1.71) and after adjusting for elevated-hsCRP (OR 1.29, 95%CI: 1.02-1.65). Elevated hs-CRP is significantly associated with MetS (OR 2.31, 95%CI: 1.95-2.76). There was no significant interaction effect of hs-CRP in the PCOS-MetS association. Conclusions: Prevalence of PCOS (self-reported and signs) was 12% in our sample of Hispanic/Latina women, which is consistent with the previous findings in non-Hispanic whites. Both PCOS (self-reported diagnosis and signs) and elevated hs-CRP were significantly associated with higher prevalence of MetS and could indicate women at metabolic disease risk.

STUDY QUESTIONDoes the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations?SUMMARY ANSWERBy including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals.WHAT IS KNOWN ALREADYAAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women.STUDY DESIGN, SIZE, DURATIONWe analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication.PARTICIPANTS/MATERIALS, SETTING, METHODSEach AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry.MAIN RESULTS AND THE ROLE OF CHANCEWe observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONExtreme AAM (18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited.WIDER IMPLICATIONS OF THE FINDINGSExpanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations.STUDY FUNDING/COMPETING INTEREST(S)Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Introduction: Several putative biomarkers of accelerated biological aging have been developed from patterns of DNA methylation in blood and other tissues (DNAm-Age scores). Some of these DNAm-Age scores have been found to be associated with age-related outcomes such as CVD and all-cause mortality, but their associations with frailty are unclear. We hypothesized that higher DNAm-Age scores measured in midlife are associated with higher odds of frailty and its components in late life. Methods: DNAm was measured at visit 2 or 3 in leukocyte DNA from 812 African American (AA) and 400 European American (EA) participants (mean age=54 years in AA, 57 years in EA), and was used to calculate three different DNAm-Age scores (Horvath, Hannum, and PhenoAge). Frailty status was assessed at visit 5, and dichotomized (frail/pre-frail or robust) using the following component criteria: slow walking speed, low grip strength, weight loss, low physical activity, and exhaustion. Logistic regression tested the associations of DNAm-Age scores, as the predictors of frailty status or each frailty component. Model 1 adjusted for visit 2 or 3 age, sex, education, white blood cell count, cell type proportions, and technical variables and model 2 additionally adjusted for BMI, smoking, alcohol, and visit 5 CHD, stroke, hypertension, and T2D. Inverse probability weights accounted for cohort attrition prior to frailty assessment. The Bonferroni-corrected threshold for statistical significance was set to p Results: In African American participants, a 4-year increase in the PhenoAge score in midlife was associated with frailty in late life (OR=1.21, 95% CI=1.09, 1.35, p=3E-4) in model 1, which was attenuated in model 2 (OR=1.13, 95% CI=1.02, 1.26, p=2.4E-2), and with physical activity (model 2 OR=1.32, 95% CI=1.13-1.53, p=4E-4); a 4-year increase in the Hannum score was associated with the exhaustion and grip strength components (OR=1.33, 95% CI=1.13-1.57, p=6E-4; OR=1.38, 95% CI=1.16-1.64, p=3E-4, respectively). In European American participants, the DNAm-Age scores were not associated with frailty however a 4-year increase in both the Horvath and Hannum scores was associated with the weight loss component (model 2 OR=1.56, 95% CI=1.20-2.02, p=9E-4; OR=2.37, 95% CI=1.49-3.76, p=2E-4), respectively. Conclusions: In African American ARIC participants, a higher mid-life PhenoAge score was associated with higher odds of frailty/pre-frailty in late life, consistent with accelerated biological aging, but was not significant after further adjustment. The Horvath, Hannum, and PhenoAge scores were associated with some frailty components in African American and European American ARIC participants, consistent with accelerated biological aging. Following replication, future studies should examine the causal relationship between DNAm-Age, frailty, and frailty components.

Introduction: Individuals with obesity are thought to be protected against some chronic disease as long as they do not incur metabolic health (MH) conditions. A new epigenetic biomarker of accelerated biological aging and health span, PhenoAge, was developed using DNA methylation (DNAm) markers. We hypothesized that obesity would be associated with higher PhenoAge than normal weight and overweight individuals only in the presence of MH conditions. Methods: DNAm was measured in leukocyte DNA for 2,454 African American participants (mean age=56.4 years) and used to calculate PhenoAge. BMI status was categorized as normal weight, overweight, and obese and MH was categorized by 0, 1, or at least 2 of the following: coronary heart disease, stroke, hypertension, type-2 diabetes, and hyperlipidemia. Linear regression tested the cross-sectional association of PhenoAge with BMI and MH, adjusting for sociodemographic variables, smoking, and technical variables. Stratified analyses by MH status were conducted to illustrate the statistical effects of BMI status in adults with and without MH conditions. Results: Participants with obesity had approximately 8 months higher PhenoAge compared to normal weight (β=0.68, 95% CI=0.21, 1.14, p=4.1E-3), and those with one (β=0.55, 95% CI=0.15, 0.94, p=6.4E-3) or at least 2 (β=0.81, 95% CI=0.38, 1.25, p=2E-4) MH conditions also had higher PhenoAge compared to those with 0 conditions. Figure 1 shows increments in PhenoAge with increments in number of MH conditions regardless of BMI. PhenoAge was significantly higher for obese compared to overweight for 0 and 1 MH conditions, but not compared to normal weight. Conclusions: In African American adults, both obesity status and presence of MH conditions were associated with a higher PhenoAge, suggesting metabolically healthy obesity is not entirely benign. Further phenotyping of the “metabolic health” obese condition is warranted to understand its relevance for healthspan.

Previous US population-based studies have found that body weight may be underestimated when self-reported. However, this research may not apply to all US Hispanics/Latinos, many of whom are immigrants with distinct cultural orientations to ideal body size. We assessed the data quality and accuracy of self-reported weight in a diverse, community-based, US sample of primarily foreign-born Hispanic/Latino adults.Using baseline data (2008-2011) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we described the difference between contemporaneous self-reported and measured current body weight (n = 16,119) and used multivariate adjusted models to establish whether the observed trends in misreporting in potential predictors of inaccuracy persisted after adjustment for other predictors. Last, we described the weighted percentage agreement in body mass classification using either self-reported or measured weight (n = 16,110).Self-reported weight was well correlated with (r = 0.95) and on average 0.23 kg greater than measured weight. The range of this misreporting was large and several factors were associated with misreporting: age group, gender, body mass categories, nativity, study site by background, unit of self-report (kg or lb), and end-digit preference. The percentage agreement of body mass classification using self-reported versus measured weight was 86% and varied across prevalent health conditions.The direction of misreporting in self-reported weight, and thus the anticipated bias in obesity prevalence estimates based on self-reported weights, may differ in US Hispanic/Latinos from that found in prior studies. Future investigations using self-reported body weight in US Hispanic/Latinos should consider this information for bias analyses.See video abstract at, http://links.lww.com/EDE/B276.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p&nbsp

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist- to-hip ratio, and waist-to-height ratio adjusted for body mass index, in 2684 African American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated Cytosine-phosphate-Guanine methylation sites (CpGs) among adults using the Women’s Health Initiative and Framingham Heart Study participants (combined N=5743) and generalized associations in adolescents from The Raine Study (N=820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and 2 in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1, and RAP1GAP2 that had not previously been associated with obesity-related traits.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently

Introduction: DNA methylation age acceleration (DNAmAA) scores, which are epigenetic biomarkers of aging and physiological responses to environmental factors such as lifestyle and health behaviors, have been previously shown to be associated with cardiovascular disease (CVD) outcomes and all-cause mortality. Life’s Simple 7 (LS7) is a tool promoted by the American Heart Association that summarizes individual adherence to seven key cardiovascular health and lifestyle metrics. We hypothesized that greater LS7 adherence would be associated with lower DNAmAA, consistent with slower biological aging. Methods: Associations between DNAmAA and LS7 were estimated separately in 2,312 African American (AA) and 1,036 European American (EA) adult participants in the Atherosclerosis Risk in Communities (ARIC) study. Visit 1 (mean age = 53 yrs in AA adults, 56 yrs in EA adults) LS7 was calculated for each participant, with 0, 1, or 2 points assigned by adherence to each component: smoking status, body mass index, physical activity, diet, plasma cholesterol, blood pressure, and fasting glucose . The summed score was categorized as inadequate (0-4), intermediate (5-9), or ideal (10-14) LS7 status. Three different previously published DNAmAA scores (Horvath, Hannum, and PhenoAge), were calculated using data from the Illumina HM450K BeadChip on stored frozen leukocytes available at visit 2 or 3 (approximately 3-6 years later). Linear regression models tested the association of LS7 category with DNAm scores, adjusting for sex, chronological age, education, income, study center, alcohol use , white blood cell count , imputed WBC type proportions using the Houseman method, Illumina HumanExome Beadchip principal components for genetic ancestry , and Illumina HM450K control probe principal components for technical adjustment. The Bonferonni-corrected threshold for statistical significance across the six tests was set to p Results: Among AA adults, ideal LS7 status (compared to poor status) was associated with a 1 year lower PhenoAge acceleration (β=-1.03; 95%CI=-1.70, -0.35; p=0.003), but was not significantly associated with Horvath or Hannum DNAmAA scores. In EA adults, ideal LS7 adherence was not significantly associated with any of the three DNAmAA scores, but the direction and magnitude of the PhenoAge acceleration association in EA was similar to that in AA (β=-0.96; 95%CI=-2.66, 0.73; p=0.27). Conclusions: African American adults with ideal LS7 status had lower PhenoAge acceleration than African Americans who did not, suggesting that heart-healthy lifestyles may slow biological aging processes in this population. Future studies should examine the prospective associations of changes in healthy lifestyle and changes in epigenetic biomarkers of aging as well as modifiers of this relationship.

Acculturation markers, such as language use, have been associated with Latino depression. Language use may change between generations; however, few studies have collected intergenerational data to assess how language differences between generations impact depression. Using the Niños Lifestyle and Diabetes Study (2013-2014), we assessed how changes in Spanish language use across two generations of Mexican-origin participants in Sacramento, California, influenced offspring depressive symptoms (N = 603). High depressive symptoms were defined as CESD-10 scores ≥ 10. We used log-binomial and linear-binomial models to calculate prevalence ratios and differences, respectively, for depressive symptoms by language use, adjusting for identified confounders and within-family clustering. Decreased Spanish use and stable-equal English/Spanish use across generations protected against depressive symptoms, compared to stable-high Spanish use. Stable-low Spanish use was not associated with fewer depressive symptoms compared to stable-high Spanish use. Exposure to multiple languages cross-generationally may improve resource access and social networks that protect against depression.

Obesity is a pandemic that has increased exponentially during the past decades due in large part to recent changes in lifestyle and food delivery systems. Yet, there is still a great variability in the burden of obesity across ancestral populations. For example, in the USA prevalence estimates of adult obesity vary from 13 to 48% in Asian Americans and African Americans.1 Such variable observations within the same obesogenic environment have motivated a wide array of inquiry into the genetic, epigenetic and social determinants of obesity, and their complex interactions with modern lifestyles and food systems.

US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a “genetic-analysis group” variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.

PURPOSE OF REVIEW: The prevalence of obesity continues to rise, fueling a global public health crisis characterized by dramatic increases in type 2 diabetes, cardiovascular disease, and many cancers. In the United States, several minority populations, who bear much of the obesity burden (47% in African Americans and Hispanic/Latinos, compared to 38% in European descent groups), are particularly at risk of downstream chronic disease. Compounding these disparities, most genome-wide association studies (GWAS) – including those of obesity – have largely been conducted in populations of European or East Asian ancestry. In fact, analysis of the GWAS catalog found that while the proportion of participants of non-European or non-Asian descent had risen from 4% in 2009 to 19% in 2016, African ancestry participants are still just 3% of GWAS, Hispanic/Latinos are

Background Transgenerational epigenetic inheritance has been posited as a possible contributor to the observed heritability of metabolic syndrome (MetS). Yet the extent to which estimates of epigenetic inheritance for DNA methylation sites are inflated by environmental and genetic covariance within families is still unclear. We applied current methods to quantify the environmental and genetic contributors to the observed heritability and familial correlations of four previously associated MetS methylation sites at three genes (CPT1A, SOCS3 and ABCG1) using real data made available through the GAW20. Results Our findings support the role of both shared environment and genetic variation in explaining the heritability of MetS and the four MetS cytosine-phosphate-guanine (CpG) sites, although the resulting heritability estimates were indistinguishable from one another. Familial correlations by type of relative pair generally followed our expectation based on relatedness, but in the case of sister and parent pairs we observed nonsignificant trends toward greater correlation than expected, as would be consistent with the role of shared environmental factors in the inflation of our estimated correlations. Conclusions Our work provides an interesting and flexible statistical framework for testing models of epigenetic inheritance in the context of human family studies. Future work should endeavor to replicate our findings and advance these methods to more robustly describe epigenetic inheritance patterns in human populations.

Even though there has been great success in identifying lipid-associated single-nucleotide polymorphisms (SNPs), the mechanisms through which the SNPs act on each trait are poorly understood. The emergence of large, complex biological data sets in well-characterized cohort studies offers an opportunity to investigate the genetic effects on trait variability as a way of informing the causal genes and biochemical pathways that are involved in lipoprotein metabolism. However, methods for simultaneously analyzing multiple omics, environmental exposures, and longitudinally measured, correlated phenotypes are lacking. The purpose of our study was to demonstrate the utility of the structural equation modeling (SEM) approach to inform our understanding of the pathways by which genetic variants lead to disease risk. With the SEM method, we examine multiple pathways directly and indirectly through previously identified triglyceride (TG)-associated SNPs, methylation, and high-density lipoprotein (HDL), including sex, age, and smoking behavior, while adding in biologically plausible direct and indirect pathways. We observed significant SNP effects (P

Foreign-born Hispanics have better cardiometabolic health upon arrival in the US than their US-born counterparts, yet this advantage diminishes as duration of residence in the US increases. Underlying mechanisms explaining this paradox have been understudied. Using data from the Sacramento Area Latino Study on Aging (SALSA), this study examined immigration history (immigrant generation and duration of US residence) in relation to biomarkers of inflammation (interleukin-6 (IL-6), soluble forms of type 1 and 2 receptors of tumor necrosis factor-alpha (sTNF-R1 and sTNF-R2), C-reactive protein (CRP), leptin, adiponectin) in a sample of 1,290 predominantly Mexican-origin immigrants. Second and ≥3rd generation immigrants had higher IL-6 and leptin levels than 1st generation immigrants living in the US for less than 15years (2nd generation percent difference=45.9; 95% CI: 24.7, 70.7 and 3rd generation percent difference=41.8; 95% CI: 17.7, 70.4). CRP and sTNF-R1 levels were higher among ≥3rd generation immigrants than 1st generation immigrants with less than 15years of US residency. Worse inflammatory profiles were observed among Mexican-origin immigrants with longer US immigration histories, independent of health, and behavioral factors. Additional research is warranted to understand the factors that shape trajectories of biological risk across generations of Hispanics.

Background Genome-wide association studies have implicated the transcription factor 7-like 2 (TCF7L2) gene in type 2 diabetes risk, and more recently, in decreased body mass index. Given the contrary direction of genetic effects on these two traits, it has been suggested that the observed association with body mass index may reflect either selection bias or a complex underlying biology at TCF7L2. Methods Using 9031 Hispanic/Latino adults (21–76 years) with complete weight history and genetic data from the community-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Baseline 2008–2011), we estimated the multivariable association between the additive number of type 2 diabetes increasing-alleles at TCF7L2 (rs7903146-T) and body mass index. We then used structural equation models to simultaneously model the genetic association on changes in body mass index across the life course and estimate the odds of type 2 diabetes per TCF7L2 risk allele. Results We observed both significant increases in type 2 diabetes prevalence at examination (independent of body mass index) and decreases in mean body mass index and waist circumference across genotypes at rs7903146. We observed a significant multivariable association between the additive number of type 2 diabetes-risk alleles and lower body mass index at examination. In our structured modeling, we observed non-significant inverse direct associations between rs7903146-T and body mass index at ages 21 and 45 years, and a significant positive association between rs7903146-T and type 2 diabetes onset in both middle and late adulthood. Conclusions Herein, we replicated the protective effect of rs7930146-T on body mass index at multiple time points in the life course, and observed that these effects were not explained by past type 2 diabetes status in our structured modeling. The robust replication of the negative effects of TCF7L2 on body mass index in multiple samples, including in our diverse Hispanic/Latino community-based sample, supports a growing body of literature on the complex biologic mechanism underlying the functional consequences of TCF7L2 on obesity and type 2 diabetes across the life course. Electronic supplementary material The online version of this article (10.1186/s40608-018-0200-x) contains supplementary material, which is available to authorized users.

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

Objective:Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.Subjects:Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.Results:We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P

Summary/AbstractGenome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development, and clinical guidelines. However, the dominance of European-ancestry populations in GWAS creates a biased view of the role of human variation in disease, and hinders the equitable translation of genetic associations into clinical and public health applications. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioral phenotypes in 49,839 non-European individuals. Using strategies designed for analysis of multi-ethnic and admixed populations, we confirm 574 GWAS catalog variants across these traits, and find 38 secondary signals in known loci and 27 novel loci. Our data shows strong evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts, and insights into clinical implications. We strongly advocate for continued, large genome-wide efforts in diverse populations to reduce health disparities.

Elevated levels of fasting glucose and fasting insulin in non-diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine-mapping genetic study of glycaemic traits would identify novel and population-specific associations that were previously undetectable by European-centric studies. A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic-specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation. Previously reported SNP associations were significantly replicated (p ≤ 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513. These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries. The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000356.v1.p1

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1–3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4–10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States—where minority populations have a disproportionately higher burden of chronic conditions13—the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Childhood obesity is a global health concern due to its potential to increase cardiometabolic risk across the life course. In the United States (US) the burden of childhood obesity is highest among Hispanic/Latinos, in particular children or adolescents of Mexican descent. Although the genetic epidemiology of childhood obesity has been studied previously, the potential for novel childhood obesity loci in Hispanic/Latinos and the generalizability of previously reported loci to Hispanic/Latino children and adolescents are still unknown. Thus we aimed to conduct a genome-wide association study of childhood obesity in 1,612 Hispanic/Latino children and adolescents (2-18 years) collected as part of one Mexican (n=794 Mexico City Study) and two US (n=362 Children’s Hospital of Philadelphia; n=456 Viva La Familia Study) studies, and to generalize 11 previously reported childhood obesity loci from European descent samples to our Hispanic/Latino samples. Obesity cases and controls were defined by BMI-for-age percentiles based on the Centers for Disease Control and Prevention smoothed and sex-specific growth curves from 2000, wherein cases had percentiles ≥95 th and controls had percentiles ≤85 th . Each study performed a genome-wide logistic regression analysis of single nucleotide polymorphism (SNPs) after adjusting for sex, population stratification and relatedness, as applicable. We combined study results for SNPs >10 minor allele counts and imputation quality ≥0.5 using fixed-effect inverse-variance weighted meta-analysis. A priori, we estimated that in our sample (n effective =1,498) we would have >80% power to detect common SNPs (>15% minor allele frequency) across the genome (p-8 ) that increase the odds of childhood obesity of 55% per risk allele. Generalizability at 11 known childhood obesity loci was defined as p-6 ), including a SNP that associated with an increased odds of childhood obesity of 54% per risk allele (73% frequent) at ARHGAP21, which is expressed in an enhancer region in brain, muscle and adipose tissues and has been previously implicated with trunk fat mass in Viva la Familia at another SNP (r 2 SEC16B and TMEM18 generalized to Hispanic/Latinos (p≤0.01), corresponding to a 27% and 40% increased odds of obesity per risk allele (22-88% frequency). These preliminary results suggest the presence of novel loci for childhood obesity and the generalizability of genetic loci discovered in samples of European descent to Hispanic/Latinos, albeit with stronger effect sizes. Future work will attempt to identify additional Hispanic/Latino obesity cases and controls to replicate the suggestive associations.

Background/objectivesCentral adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.Subjects/methodsTo identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.ResultsOf the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.ConclusionsOf 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

Objective: Several genome–wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups. Design and Methods: As part of the “Population Architecture using Genomics and Epidemiology (PAGE)” Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined “replicating SNPs” (in European Americans) and “generalizing SNPs” (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI. Results: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians. Conclusion: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P0.01 for ANM analyses and P0.017 for AM analyses.We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P−8) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

The CVD health of US Hispanic/Latino individuals—the second largest ethnic group in the US—is a top public health priority. Although Hispanic/Latino individuals have higher rates of obesity than non-Hispanic Whites, the pattern of adulthood weight gain in this diverse group and its relationship with CVD risk factors are unknown. We examined trajectories of weight gain and the associations of these trajectory classes with dyslipidemia, diabetes, physical inactivity, poor diet quality and hypertension among HCHS/SOL participants baseline ages 50-74 years. HCHS/SOL is a population-based cohort study of self-identified Hispanic/Latino adults from four urban US communities. At baseline HCHS/SOL participants were asked to recall/report their body weight at 21, 45, 65 years old, last year and currently (kg or lb, 2008-2011). We used a finite mixture model (selected for ≤10 classes, ≥3% of sample per class and favored by change in the Bayesian Information Criterion) to assign individuals with two or more self-reported weights to their most likely trajectory class. We then described the distribution of class membership across categories of CVD risk factors (Wald Chi-square test). All analyses accounted for the complex sampling design of HCHS/SOL and were adjusted for baseline age, height, and gender. There were 6,779 individuals who reported weights at 2-5 time points (25,687 observations). In the final four-group quadratic trajectory mixture model the two most common classes comprised individuals who on average maintained a normal weight in adulthood (18.5-24.9kg/m 2 ) but became overweight (≥25kg/m 2 ) in their 50s (class 1: 38% of sample), or who gained enough weight in early adulthood to become overweight by their 30s and obese (≥30kg/m 2 ) by their 50s (class 2: 43%). The other two classes were characterized by more severe weight gain across adulthood, but these classes were less common (class 3: 16%; class 4: 3%). Individuals grouped in class 3 on average had a normal weight in their 20s, gained weight steadily, and became obese by their 40s. Class 4 represented the most dynamic trajectory, wherein individuals began overweight in their 20s and gained >40kg by their late 50s when they began to lose weight. At baseline dyslipidemia, untreated diabetes (p In summary our results indicate that although weight gain was ubiquitous, more than a third of participants aged 50-74 years belonged to a trajectory class that did not develop obesity during adulthood. Trajectories of extreme weight gain were associated with a higher burden of CVD risk factors. Future studies should investigate modifiable factors that influence trajectories and could serve as targets for public health interventions in CVD.