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 ancestry
. 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-specific
. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations
. 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 conditions
-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.
Immigrants are an important part of many high-income nations, in that they contribute to the sociocultural tapestry, economic well-being, and demographic diversity of their receiving countries and ...communities. Yet, genomic studies to date have generally focused on non-immigrant, European-ancestry populations. Although this approach has proven fruitful in discovering and validating genomic loci, within the context of racially/ethnically diverse countries like the United States—wherein half of immigrants hail from Latin America and another quarter from Asia—this approach is insufficient. There is a persistent diversity gap in genomic research in terms of both current samples and genome-wide association studies, meaning that the field’s understanding of genetic architecture and gene-environmental interactions is being hampered. In this commentary, I provide motivating examples of recent research developments related to the following: (1) how the increased ancestral diversity, such as seen among Latin American immigrants, improves power to discover and document genomic loci, (2) informs how environmental factors, such as immigration-related exposures, interact with genotypes to influence phenotypes, and (3) how inclusion can be promoted through community-engaged research programs and policies. I conclude that greater inclusion of immigrants in genomic research can move the field forward toward novel discoveries and interventions to address racial/ethnic health disparities.
Genomic studies to date have focused primarily on non-immigrant populations, and in this commentary, I provide motivating examples on the benefit of promoting the inclusion of immigrant populations in genomics. I conclude that greater diversity and inclusion can lead to additional discoveries and inform interventions to address racial/ethnic health disparities.
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 Niños 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.
Summary Background Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a ...neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5α-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease. Methods We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0·5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov , NCT00303446. Findings 50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4·5% (−0·30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3% (0·14 kg/kg); the difference between groups (5·8%, 95% CI −5·9 to 17·6; p=0·28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, −3·6%, vs dutasteride, 2·1%; p=0·01), whereas the mental component summary favoured placebo (3·3% vs −3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events. Interpretation Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials. Funding US National Institutes of Health.
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.
Immigration enforcement may disrupt access to health care, potentially increasing hospitalizations for Ambulatory Care Sensitive Conditions (ACSC). We aimed to assess the effect of local-level 287(g) ...immigration enforcement on North Carolina pediatric ACSC hospitalizations. Pediatric (< 19 year) ACSC hospitalizations were identified based on ICD-9 codes. We compared ACSC hospitalizations pre and post 287(g) implementation using a difference-in-difference analysis of Fiscal Year (FY)2006-2009 data. We used multi-level models to assess the effects of 287(g) programs on ACSC hospitalizations during FY2011-2015. Difference-in-difference analyses showed that ACSC hospitalizations increased by more than 2.48% in the year following 287(g) implementation (95% CI: 0.99%, 3.97%). Among the counties that had ever implemented a 287(g) program, the ACSC-increasing effect of an active 287(g) program was greatest in counties with a shorter tenure of their 287(g) program and for Hispanic/Latino children/adolescents. Our findings underscore the importance of describing the effects of local-level immigration enforcement on pediatric access to care and potentially avoidable hospitalizations.
Abstract Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index ...(BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987–1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent visit (1990–1995). We then utilized structural equation modeling (SEM) to test whether identified sites mediated the association between earlier SES and BMI in sex-stratified models adjusted for demographic and risk factor covariates. Independent replication and meta-analyses were conducted using the Jackson Heart Study (JHS, n = 874, mean age 51 years, 2000–2004). Three CpG sites near MAD1L1, KDM2B, and SOCS3 (cg05095590, cg1370865, and cg18181703) were suggestively associated (P-value < 1.3×10−5) in ARIC and at array-wide significance (P-value < 1.3×10−7) in a combined meta-analysis of ARIC with JHS. SEM of these three sites revealed significant indirect effects in females (P-value < 5.8×10−3), each mediating 7%–20% of the total effect of SES on BMI. Nominally significant indirect effects were observed for two sites near MAD1L1 and KDM2B in males (P-value < 3.4×10−2), mediating −17 and −22% of the SES-BMI effect. These results provide further evidence that epigenetic modifications may be a potential pathway through which SES may “get under the skin” and contribute to downstream health disparities.
Abstract Context Polycystic ovary syndrome (PCOS) is a multifaceted endocrine disorder with reproductive and metabolic dysregulation. PCOS has been associated with inflammation and metabolic syndrome ...(MetS); however, the moderating effects of inflammation as measured by C-reactive protein (CRP) and menopause on the PCOS-MetS association have not been studied in Hispanic/Latinas with PCOS who have a higher metabolic burden. Objective We studied the cross-sectional association between PCOS and (1) MetS in 7316 females of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), (2) subcomponents of MetS including impaired fasting glucose (IFG) and elevated triglycerides (TGL), and (3) effect modification by menopausal status and CRP. Design The HCHS/SOL is a multicenter, longitudinal, and observational study of US Hispanic/Latinos. Our study sample included females from visit 2 with self-reported PCOS and MetS (ages 23-82 years). Results PCOS (prevalence = 18.8%) was significantly associated with MetS prevalence odds ratio odds ratio (OR) = 1.41 (95% confidence interval: 1.13-1.76), IFG and TGL (OR = 1.42 (1.18-1.72), OR = 1.48 (1.20-1.83), respectively. We observed effect modification by menopausal status (ORpre = 1.46, Pint = .02; ORpost = 1.34, Pint = .06) and CRP (ORelevated = 1.41, Pint = .04; ORnormal = 1.26, Pint = .16) on the PCOS-MetS association. We also observed a superadditive interaction between CRP and PCOS, adjusting for which resulted in an attenuated effect of PCOS on MetS (OR = 1.29 0.93-1.78). Conclusion Hispanic/Latino females with PCOS had higher odds of MetS, IFG, and elevated TGL than their peers without PCOS. Interaction analyses revealed that the odds of MetS are higher among PCOS females who have premenopausal status or high inflammation. Interventions in Hispanic/Latinas should target these outcomes for effective management of the disease.
Background The Hispanic/Latino population experiences socioeconomic disadvantages across the lifespan. Yet, little is known about the role of these disadvantages in cardiovascular health (CVH). We ...assessed the association of lifecourse socioeconomic position (SEP) with ideal CVH and change in Hispanic/Latino adults. Methods and Results We used longitudinal data from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Childhood SEP was determined using parental educational attainment. Adult SEP was determined through an index combining participants' education, occupation, income, and assets at baseline. We classified participants into 4 socioeconomic mobility categories (eg, stable low or high SEP, upward or downward mobility). Using the 4 health factors of the American Heart Association “Life's Essential 8,” we built a score of ideal CVH at baseline and the 6‐year follow‐up. Linear mixed‐effects models using inverse probability weighting were fitted to assess the main associations. Higher childhood SEP was associated with higher ideal CVH at baseline (β for high school versus <high school, 3.57 95% CI, 1.76–5.57) and (>high school versus <high school, 3.76 95% CI, 1.99–5.52). Middle (β for middle versus low SEP, 3.57 95% CI, 1.65–5.49) and high adult SEP (β for high versus low SEP, 5.05 95% CI, 2.55–7.55) were also associated with higher ideal CVH. Socioeconomic mobility was also associated with higher ideal CVH. No life‐course SEP exposure was associated with the change in ideal CVH over a 6‐year period. Conclusions Although high childhood and adult SEP and socioeconomic mobility were associated with higher levels of ideal CVH, they were not associated with change in ideal‐CVH.
The link between childhood adversity and adulthood depression is well-established; however, the underlying mechanisms are still being explored. Recent research suggests biological age may mediate the ...relationship between childhood adversity and depression in later life. This study examines if biological age mediates the relationship between childhood adversity and depression symptoms using an expanded set of biological age measures in an urban population-based cohort. Data from waves 1-3 of the Detroit Neighborhood Health Study (DNHS) were used in this analysis. Questions about abuse during childhood were coded to form a childhood adversity score similar to the Adverse Childhood Experience measure. Multiple dimensions of biological age, defined as latent variables, were considered, including systemic biological age (GrimAge, PhenoAge), epigenetic age (Horvath, SkinBlood), and immune age (cytomegalovirus, herpes simplex virus type 1, C-reactive protein, interleukin-6). Depression symptoms, modeled as a latent variable, were captured through the Patient Health Questionnaire-9 (PHQ-9). Models were adjusted for age, gender, race, parent education, and past depressive symptoms. Total and direct effects of childhood adversity on depression symptoms and indirect effects mediated by biological age were estimated. For total and direct effects, we observed a dose-dependent relationship between cumulative childhood adversity and depression symptoms, with emotional abuse being particularly influential. However, contrary to prior studies, in this sample, we found few direct effects of childhood adversity on biological age or biological age on depression symptoms and no evidence of mediation through the measures of biological age considered in this study. Further research is needed to understand how childhood maltreatment experiences are embodied to influence health and wellness.
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