Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus

Abstract

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.

Keywords: Alzheimer disease; Chromosome 9; Genetic linkage; Puerto Ricans; Underserved populations.

Fig. 1.

Multipoint linkage peak on chromosome 9. x-axis denotes physical position in base pairs, and y-axis denotes the HLOD score. Blue and red lines illustrate the linkage regions from independent Israeli-Arab and non-Hispanic Whites family studies. Lines on the x-axis align with the linkage region and on the y-axis align with corresponding HLOD score.

Fig. 2.. Pedigree of family 87663.

Individuals diagnosed with Alzheimer disease are denoted in black and with mild cognitive impairment in grey. The first number beneath each individual indicates the personal ID and the second number shows age at onset for individuals with disease or the age at examination for unaffected family members. The third row indicates the APOE genotype and the last row shows the genotypes of the missense variant rs35199210 (UNC13B).