👤 Chris Gignoux

To determine whether genetic ancestry modulates Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023. Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (Aβ In the full cohort, Genetic ancestry modifies the effect of Show less

To identify novel genetic loci associated with differences in serum etonogestrel concentrations among contraceptive implant users. We conducted a cross-sectional analysis in which we enrolled healthy, reproductive-aged (age 18-45 years) participants who had been using etonogestrel implants for 12-48 months. Participants underwent a single-time blood draw for measurement of serum etonogestrel concentrations by liquid chromatography-tandem mass spectrometry and the extraction of DNA from whole blood. We genotyped participants using the Illumina Infinium Global Diversity Array with Enhanced PGx and imputed genotyping results using the TOPMed imputation server. We performed genome-wide complex trait analysis using a linear mixed model leave-one-chromosome-out association analysis to identify genetic variants associated with serum etonogestrel concentrations. We enrolled 900 etonogestrel implant users, with a median age of 22.3 years (range 18.0-41.5 years), median body mass index (BMI) 26.0 (range 18.5-52.0), and median duration of implant use 27 months (range 12-48 months). Most participants self-reported their race as White (49.3%) and ethnicity as Hispanic or Latina (52.9%). Participants had a median serum etonogestrel concentration of 126.9 pg/mL (range 39.4-695.1 pg/mL). Including BMI, duration of implant use, and three principal components as covariates in the genome-wide complex trait analysis, we identified no genetic variants with minor allele frequencies at or above 5% that were associated with serum etonogestrel concentrations at genome-wide significance ( Despite enhanced coverage for known pharmacogenomic variants, we found no significant associations between interindividual variability in contraceptive implant pharmacokinetics and genetic loci directly involved in exogenous steroid hormone metabolism. ClinicalTrials.gov, NCT03092037. Show less

We carried out an admixture mapping study of lipid traits in two samples from Mexico City. Native American locus ancestry was significantly associated with triglyceride levels in a broad region of chromosome 11 overlapping the BUD13, ZNF259 and APOA5 genes. In our fine-mapping analysis of this region using dense genome-wide data, rs964184 is the only marker included in the 99% credible set of SNPs, providing strong support for rs964184 as the causal variant within this region. The frequency of the allele associated with increased triglyceride concentrations (rs964184-G) is between 30-40% higher in Native American populations from Mexico than in European populations. The evidence currently available for this variant indicates that it may be exerting its effect through three potential mechanisms: 1) modification of enhancer activity, 2) regulation of the expression of several genes in cis and/or trans, or 3) modification of the methylation patterns of the promoter of the APOA5 gene. Show less