Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation inPSEN1With Familial Alzheimer Disease Among Caribbean Hispanics

Abstract

IMPORTANCE The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures.OBJECTIVE To identify genetic variants that modify age at onset of AD. DESIGN, SETTING, AND PARTICIPANTS Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics. MAIN OUTCOMES AND MEASURES Age at onset of AD.RESULTS Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1.CONCLUSIONS AND RELEVANCE Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD.

Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

“…Studies in knock-out mouse models have established that the gene TCRα has an important role in adult neurogenesis [Huang and others 2010], particularly in the hippocampus, an area of the brain involved in the HAND phenotype. The SH3RF3 gene (and the SH3 domain) has been associated with age of onset in familial Alzheimer’s disease [Lee and others 2015]. At a type I error cut-off of p<10 −4 , 8 SNPs were associated with both binary GDS and continuous GDS.…”

Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

“…The latter has been reported as a genetic modifier affecting both AAO and circulating levels of progranulin in FTD patients carrying Granulin mutations [34, 35]. Another example of genetic modifiers of AAO is the one recently reported in PSEN1 -related Alzheimer’s disease [36]. …”

Unusually long duration and delayed penetrance in a family with FTD and mutation in MAPT (V337M)

“…Apolipoprotein E is one such genetic factor influencing AD, but its role in FTD is unclear and controversial [Bernardi et al, 2006; Seripa et al, 2011; Hernández et al, 2014]. Lee et al [2015] have reported three genes (SNX25, PDLIM3, SORBS2) modifying age of onset in a specific mutation (G206A) in PSEN1 in familial AD, but the effect of these genes in FTD is unknown. A single nucleotide polymorphism (SNP) in TMEM106B has been shown to modify penetrance in GRN- related FTD [Finch et al, 2011] and motor neuron versus behavioral expression in C9orf72 -related ALS/FTD [van Blitterswijk et al, 2014], but reported to have no effect in MAPT-related FTD [Finch et al, 2011].…”