Project 2: Multi-Ethnic Analysis for Alzheimer Disease

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PROJECT SUMMARY/ABSTRACT: PROJECT 2 (Multi-Ethnic Analysis for Alzheimer Disease) Alzheimer's disease (AD)’s etiology is still relatively unexplained but substantial evidence supports a strong genetic component. Most AD genetic studies have focused on European (EU) descent individuals, despite Hispanic/Latinx (HL, genetically admixed of EU, African (AF) and Native American (NA) ancestry) and African Americans (AA, genetically admixed of EU and AF ancestry) having higher prevalence and incidence of AD. Thus, it is important to understand how ancestry affects AD risk among diverse populations to provide better models of risk. Overall, we hypothesize that diverse populations harbor novel AD risk/protective alleles that are rare or absent in other populations or that they have modifiers that alter the effects of common risk alleles, and specifically that AF and NA ancestries enhances AD risk. ʺRecruitment and Retention for Alzheimer’s Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP) will add new, diverse cohorts that augment the existing pool of genomic data. To test our hypothesis, we will perform admixture mapping in AA and HL, assuming causal variants/genes are more frequently on chromosomal segments inherited from the ancestral population with higher AD prevalence. We will also investigate universal genetic loci (i.e. those that confer risk in most or all populations) by performing a large trans-ethnic study that includes AA, HL, as well as EU and AF ancestral populations. This approach will boost statistical power, detection of rare variant and dissection of AD genetic architecture within populations. We will also test whether associating and/or modifying loci differ from the genomic background in terms of past selective events that may have shifted AD risk. To study the diversity of AD genetic risk, we will: 1) Determine the AF and NA origins of genetic variation in AD, using admixed populations and investigate ethnic-specific modifiers. We will estimate global and local ancestry in each HL and AA cohort separately, in order to investigate their association with AD and prioritize the genomic segments where higher AF or NA ancestry confers higher AD risk. These segments will be fine-mapped employing resources developed in Project 1 and with ancestry-aware association tests. We will also examine whether the effects of known or newly-identified AD-associated loci are altered by ancestry background. 2) We will perform trans-ethnic meta-analysis across AF, AA, HL, NHW cohorts using single-marker and gene- based outputs from Project 1 but also we will meta-analyze local ancestries that are shared across admixed cohorts (e.g. AF component across AA, Puerto Ricans, Cubans etc.). Finally, 3) we will perform explicit tests of selection on AD-associated loci and their modifying loci prioritized by Project 1 and 2 and determine whether patterns of evolutionary history are consistent across diverse populations with patterns of association.