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

Neurobiol Aging. 2021 Aug;104:115.e1-115.e7. doi: 10.1016/j.neurobiolaging.2021.02.019. Epub 2021 Feb 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • C9orf72 Protein / genetics
  • Chromosomes, Human, Pair 9 / genetics*
  • Genetic Linkage*
  • Genetic Variation / genetics*
  • Genome-Wide Association Study*
  • Hispanic or Latino / genetics
  • Humans
  • Nerve Tissue Proteins / genetics
  • Whole Genome Sequencing

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Nerve Tissue Proteins
  • UNC13B protein, human