Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease

Abstract

Background: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling.

Methods: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study.

Results: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci.

Discussion: Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.

Highlights: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families.

Keywords: familial Alzheimer's disease; gene loci; genetic segregation; genome wide association studies; rare variants.

FIGURE 1

A filtering process was described in the methods to identify rare variants (gnomAD MAF less than 1%) with complete of incomplete segregation in families. Segregation was defined as being present in all affected members of a family. If a variant segregated in one family and showed incomplete segregation in another family, we required a qualifying variant to be seen only in affected members. Unaffected family members with qualifying variants were accepted if their age was ≥5 years below the age at onset of the affected carriers. **Incomplete segregation was defined as variants present in at least four affected individuals with AD in the specific cohort (AD‐FBS or EFIGA), observed in more affected than unaffected individuals, and if present in unaffected individuals if their age was ≥5 years below the age at onset of the affected carriers.