Missense and Loss of Function Variants at GWAS Loci in Familial Alzheimer’s Disease

Abstract

PURPOSEFew rare pathogenic variants have been identified in the 70+ genetic loci from genome wide association studies of late-onset Alzheimer’s disease (AD), limiting research on underlying mechanisms, risk assessment, and genetic counseling.METHODSUsing genome sequencing data from 197 families in The National Institute on Aging Alzheimer’s Disease Family Based Study (AD-FBS), and 214 families in The Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), we characterized rare coding variants predicted to highly damaging missense or loss of function variants (LoF) within known GWAS loci.RESULTSEight coding and one LoF variant segregated in 10 (5.1%) AD-FBS families and 16 coding and two LoF variants segregated in 18 (8.4%) EFIGA families.ABCA7 and AKAP9contained the most damaging variants. In 51 (25.9%) of the AD-FBS and in 26 (12.1%) of the EFIGA families,APOE-ε4was the only variant segregating with familial AD (fAD). NeitherAPOE-ε4nor missense or LoF variants were found in 44.1% of the AD-FBS and 62.1% of the EFIGA families.CONCLUSIONSAlthough rare variants were found in both family groups, many families had no gene variant segregating within the family, indicating that the genetic basis for AD has yet to be fully defined.