GENOME-WIDE LINKAGE ANALYSIS OF AFRICAN-AMERICAN ALZHEIMER DISEASE FAMILIES

Genetic studies of African-Americans (AA) with late-onset Alzheimer's disease (LOAD) have been limited, despite evidence suggesting an increased risk for Alzheimer disease (AD), and differential genetic effects across ancestral populations. We assessed 44 multi-generational AAAD families from the Research in African American Alzheimer Disease Initiative and LOAD using genome-wide linkage analysis to prioritize regions containing risk or protective genes for AAAD. We performed linkage analyses in 44 families (419 total individuals, 137 affected). Three models were assessed using Merlin software: 1) two-point parametric dominant affected-only and age-dependent penetrance models 2) multipoint parametric dominant affected-only dominant model (MPT-AO) and 3) Non parametric linkage (NPL) multipoint. Whole genome sequence (WGS) data from the AD Sequencing Project (ADSP) were available on a subset of families (N=8). WGS data were analyzed for segregation with disease and annotated for putative function. The MPT-AO model had 4 peaks over an HLOD of 1.2 with the strongest peak seen on Chromosome 7 (HLOD 2.49, four families contributing >0.58). The NPL multipoint result had 3 peaks with a LOD over 1.2 with the highest LOD on Chromosome 5 (LOD 2.16, with 3 contributing families). Families contributing to the Chromosome 7 and 5 peaks did not overlap. The Chromosome 5 region overlaps with a reported linkage region for a Dutch extended family (Ahmad, 2016). Looking at the segregation of variants in the contributing families showed a high-risk splice donor variant in CDH12 as well as a number of potentially damaging missense variants in MYO10 and PRDM9. Family specific peaks over 1.4 were seen in two families in MPT-AO model. The strongest signal localized to a region on Chromosome 12 (LOD=3.18) in the parametric dominant model. The region overlaps a previously reported linkage peak in NHW families (Scott et al., 2000) and in the ADSP Non-Hispanic White Linkage analysis (Beecham et al., 2019). Linkage analysis of AA families showed two potential consensus multipoint peaks and confirmed a previously identified family specific peak on chromosome 12. Potential segregating variants were found in families contributing to the Chromosome 5 peak region including variants in CDH12, MYO10 and PRDM9.