Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

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 (HISLA 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 three secondary signals for BMI, 28 for height, and two 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

Perceived Discrimination and Trajectories of C-Reactive Protein: The Jackson Heart Study.

INTRODUCTION: Perceiving discriminatory treatment may contribute to systemic inflammation, a risk factor of cardiovascular pathophysiology. This study evaluated the association of self-reported discrimination with changes in high-sensitivity C-reactive protein and the mediating role of adiposity. METHODS: The sample included 5,145 African-Americans, aged 21-92 years, in the Jackson Heart Study. Everyday, lifetime, and burden from perceived discrimination comprised primary predictors in 3 sets of multivariable linear regression models of baseline (2000-2004) discrimination and natural logarithm of high-sensitivity C-reactive protein. Multivariable linear mixed models assessed mean changes in natural logarithm of high-sensitivity C-reactive protein over the study period (2000-2013). Mediation was quantified by percentage changes in estimates adjusted for BMI, waist circumference, and waist-to-height ratio. Multiple imputation addressed missingness in baseline covariates and in high-sensitivity C-reactive protein taken at all 3 study examinations. Analyses were conducted in 2018. RESULTS: In cross-sectional analyses, male participants in the middle and highest tertiles of lifetime discrimination had natural logarithm of high-sensitivity C-reactive protein levels that were 0.13 (95% CI= -0.24, -0.01) and 0.15 (95% CI= -0.27, -0.02) natural logarithm(mg/dL) lower than those in the lowest tertile. In longitudinal analyses, all participants reporting more frequent everyday discrimination had a 0.07 natural logarithm(mg/dL) greater increase in natural logarithm of high-sensitivity C-reactive protein per examination than those reporting none (95% CI=0.01, 0.12). A similar trend emerged for lifetime discrimination and changes in natural logarithm of high-sensitivity C-reactive protein (adjusted mean increase per visit: 0.04 natural logarithm[mg/dL], 95% CI=0.01, 0.08). Adiposity did not mediate the longitudinal associations. CONCLUSIONS: Everyday and lifetime discrimination were associated with significant high-sensitivity C-reactive protein increases over 13 years. The physiologic response to discrimination may lead to systemic inflammation

Cumulative socioeconomic status and incident type 2 diabetes among African American adults from the Jackson heart study.

BackgroundThe cumulative socioeconomic status (SES) model posits that childhood and adult experiences accumulate to influence disease risk. While individual SES indicators such as education and income are independently associated with incident type 2 diabetes (T2D), the association of cumulative SES and incident T2D is unclear, especially in African American adults.MethodsWe utilized cohort data of African American participants (n = 3681, mean age 52.6 years) enrolled in the Jackson Heart Study from 2000 to 2013 free of T2D or cardiovascular disease at baseline (2000-2004). Cumulative SES scores at baseline were derived using six SES indicators (education, wealth, income, occupation, employment status, and mother's education) categorized as low, middle, and high. Incident T2D was defined at exam 2 (2005-2008) or exam 3 (2009-2013) based on fasting glucose ≥126 mg/dL, HbA1c ≥ 6.5, reported diabetic medication use, or self-reported physician diagnosis. Proportional hazards regression, allowing for interval censoring, was used to estimate the association between cumulative SES and incident T2D (hazard ratio(HR), 95% confidence interval (CI)) after adjustment for covariates. Sex and age differences were tested using interaction terms.ResultsThere were 544 incident T2D cases. The association between low (versus high) cumulative SES and incident T2D was not significant (HR 1.04 [95% CI 0.85, 1.28]) and did not differ by sex (p value for interaction>0.05). However, there were differences by (age p value for interaction = 0.0052 for middle-aged adults and 0.0186 for older adults). Low (versus high) cumulative SES was associated a greater hazard of incident T2D among those 20-46 years (HR 1.12 [95% CI 1.03, 1.21]), 47-59 years (HR 1.25 [95% CI 1.06, 1.47]) and those 60-93 years (HR 1.39 [95% CI 1.09, 1.78]) after adjustment for sex and family history of diabetes. Associations attenuated after adding behavioral and lifestyle risk factors.ConclusionThe association of low cumulative SES and incident T2D differed by age, which may suggest interventionist should consider impacts of SES on T2D by age

Cumulative socioeconomic status and incident type 2 diabetes among African American adults from the Jackson heart study

Background: The cumulative socioeconomic status (SES) model posits that childhood and adult experiences accumulate to influence disease risk. While individual SES indicators such as education and income are independently associated with incident type 2 diabetes (T2D), the association of cumulative SES and incident T2D is unclear, especially in African American adults. Methods: We utilized cohort data of African American participants (n = 3681, mean age 52.6 years) enrolled in the Jackson Heart Study from 2000 to 2013 free of T2D or cardiovascular disease at baseline (2000–2004). Cumulative SES scores at baseline were derived using six SES indicators (education, wealth, income, occupation, employment status, and mother's education) categorized as low, middle, and high. Incident T2D was defined at exam 2 (2005–2008) or exam 3 (2009–2013) based on fasting glucose ≥126 mg/dL, HbA1c ≥ 6.5, reported diabetic medication use, or self-reported physician diagnosis. Proportional hazards regression, allowing for interval censoring, was used to estimate the association between cumulative SES and incident T2D (hazard ratio(HR), 95% confidence interval (CI)) after adjustment for covariates. Sex and age differences were tested using interaction terms. Results: There were 544 incident T2D cases. The association between low (versus high) cumulative SES and incident T2D was not significant (HR 1.04 [95% CI 0.85, 1.28]) and did not differ by sex (p value for interaction>0.05). However, there were differences by (age p value for interaction = 0.0052 for middle-aged adults and 0.0186 for older adults). Low (versus high) cumulative SES was associated a greater hazard of incident T2D among those 20–46 years (HR 1.12 [95% CI 1.03, 1.21]), 47–59 years (HR 1.25 [95% CI 1.06, 1.47]) and those 60–93 years (HR 1.39 [95% CI 1.09, 1.78]) after adjustment for sex and family history of diabetes. Associations attenuated after adding behavioral and lifestyle risk factors. Conclusion: The association of low cumulative SES and incident T2D differed by age, which may suggest interventionist should consider impacts of SES on T2D by age

Optimism and risk of mortality among African-Americans: The Jackson heart study.

Optimism is associated with reduced mortality risk among Whites, but evidence for this relationship is limited among African-Americans, whose life expectancy is shorter than Whites. This study examined the association between optimism and mortality rate in African-Americans. Data were from African-American women (n = 2652) and men (n = 1444) in the United States from the Jackson Heart Study. Optimism was measured using the Life Orientation Test-Revised at the baseline period (2000-2004), and mortality data were obtained until 2018. Using Cox proportional hazards models, we estimated hazard ratios (HRs) of mortality by optimism level, controlling for sociodemographic factors, depressive symptoms, health conditions, and health behaviors. In secondary analyses, we evaluated potential effect modification by sex, age, income, and education. Higher optimism was related to lower mortality rates (HR = 0.85, 95% confidence interval [CI] = 0.74, 0.99), controlling for sociodemographic factors and depressive symptoms. After further adjusting for health conditions and health behaviors, associations were slightly attenuated (HR = 0.89; 95%CI = 0.77, 1.02). Stronger associations between optimism and mortality were observed in men, among those with higher income or education, and with age ≤ 55 (all ps for interaction terms <0.06). In summary, optimism was associated with lower mortality rates among African-Americans in the Jackson Heart Study. Effect modification by sociodemographic factors should be further explored in additional research considering optimism and mortality in diverse populations. Positive factors, such as optimism, may provide important health assets that can complement ongoing public health efforts to reduce health disparities, which have traditionally focused primarily on risk factors

Depressive Symptoms and Incident Heart Failure in the Jackson Heart Study: Differential Risk Among Black Men and Women

Background Associations between depression, incident heart failure (HF), and mortality are well documented in predominately White samples. Yet, there are sparse data from racial minorities, including those who are women, and depression is underrecognized and undertreated in the Black population. Thus, we examined associations between baseline depressive symptoms, incident HF, and all‐cause mortality across 10 years. Methods and Results We included Jackson Heart Study (JHS) participants with no history of HF at baseline (n=2651; 63.9% women; median age, 53 years). Cox proportional hazards models tested if the risk of incident HF or mortality differed by clinically significant depressive symptoms at baseline (Center for Epidemiological Studies–Depression scores ≥16 versus <16). Models were conducted in the full sample and by sex, with hierarchical adjustment for demographics, HF risk factors, and lifestyle factors. Overall, 538 adults (20.3%) reported high depressive symptoms (71.0% were women), and there were 181 cases of HF (cumulative incidence, 0.06%). In the unadjusted model, individuals with high depressive symptoms had a 43% greater risk of HF (P=0.035). The association remained with demographic and HF risk factors but was attenuated by lifestyle factors. All‐cause mortality was similar regardless of depressive symptoms. By sex, the unadjusted association between depressive symptoms and HF remained for women only (P=0.039). The fully adjusted model showed a 53% greater risk of HF for women with high depressive symptoms (P=0.043). Conclusions Among Black adults, there were sex‐specific associations between depressive symptoms and incident HF, with greater risk among women. Sex‐specific management of depression may be needed to improve cardiovascular outcomes

Ancestral Diversity Improves Discovery and Fine-Mapping of Genetic Loci for Anthropometric Traits-The Hispanic/Latino Anthropometry Consortium

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

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.]

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

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&nbsp;= 59,771) and generalized our findings in 9 additional studies (stage 2, n&nbsp;= 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