Wednesday, April 2, 2025
4/2/2025
Mexican Teachers Cohort Study: Genetics and Cognitive Function - ABSTRACT This is a resubmission of a U01 application for the “Alzheimer’s Disease Sequencing Project (ADSP) Follow- Up Study 2.0: The Diverse Population Initiative” (PAR-21-212). The overall goals are to: (i) contribute nearly 20,000 GWAS and 5000 whole genome sequences to ADSP from participants of the “Estudio de la Salud de las Maestras” (Mexican Teachers Cohort), and (ii) detect novel genetic drivers of cognitive function in this large Mexican cohort, in combination with existing ADSP cohorts. US Hispanics are projected to experience the largest increase in ADRDs of any ethnic group. Moreover, dementia onset occurs at younger ages, on average, in Hispanic/Latinx (HL) populations in the US; expected years lived with cognitive impairment is up to 4-8 years longer for older HL individuals, than non-Hispanic whites. Mexican-Americans represent 65% of US Hispanics; cohorts in Mexico can thus complement those in the US to maximize dementia research in diverse populations. Mexican Teachers Cohort (MTC) was established in 2006, and is an ongoing cohort of female teachers, which has maintained high followup. MTC spans 12 culturally diverse states in Mexico and was designed to support research on genetic and social determinants of health. In particular, ancestry analyses demonstrate genetic separation of Mexican from Central and South American backgrounds (Mexicans have distinct AmerIndian substructure). Thus, addition of MTC to ADSP can substantially contribute to identification of novel and relevant genes/pathways underlying health. Central to this U01, we propose to extend MTC by (i) implementing up to 2 waves of cognitive evaluations in 13,500 existing women plus 3,500 newly-recruited men, age 55+ years, and (ii) collecting blood specimens in all participants. In Aim 1, we will genotype 17,000 participants using the Illumina Global Screening Array; perform whole genome sequencing in 5000 participants age 65+ years; process/harmonize array and sequencing data. In Aim 2, we will perform discovery admixture analyses to identify global ancestry, and then local ancestry-associated regions, related to the powerful quantitative trait of global cognitive function, and secondarily to cognitive impairment (MCI+dementia); this will include fine mapping to identify credible causal variants, and replication in ADSP cohorts. We will also examine known AD-related SNPs in this large HL population. In Aim 3, we will generate measures of telomere length using TelSeq on WGS, and measures of mitochondrial DNA (mtDNA) variation (mtDNA copy number and mtDNA heteroplasmy) from WGS; we will examine associations with cognitive function and cognitive impairment, addressing differences by ancestry. Finally, in Aim 4, we will share all specimens via the NCRAD repository, and data via NIAGADS. IMPACT: The proposed application will provide a strong and sustained impact on the field by substantially broadening the platform for discovery regarding cognitive aging in Hispanic/Latinx individuals.
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