Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia

Abstract

Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer’s disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer’s disease through rare variants. Here we show that a proxy Alzheimer’s disease/dementia phenotype can capture known Alzheimer’s disease risk genes through rare variant aggregation. We generated a proxy Alzheimer’s disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer’s disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer’s disease/dementia can be used to identify genes associated with Alzheimer’s disease through rare variant aggregation.

Region-based analysis with functional annotation identifies genes associated with cognitive function in South Asians from India

“…Similar gene-based analysis studies were conducted in EA samples. One large genome-wide gene-based AD study conducted in the UK BioBank on different categories of rare missense/LoF variants found that three gene regions were associated with AD parent proxy cases, including TOMM40/APOE [55]. Notably, detection of these regions depended on resolving variants into categories of high confidence and predicted loss-of-function effects.…”

Patient with PSEN1 Glu318Gly and Other Possible Disease Risk Mutations, Diagnosed with Early Onset Alzheimer’s Disease

“…Interestingly, increased microglia activations and inflammasome formations were found in patients with TOMM40 F113L or F131L [9]. Even though TOMM40 Arg239Trp was a rare variant in a conserved region of TOMM40, its association with AD or any forms of neurodegeneration remained unclear [59].…”

The ABC's of Alzheimer risk gene ABCA7

“…A meta‐analysis in 2019 found a significant enrichment of PTC and missense mutations in patients with an OR of 2.6 and 1.8, respectively, 38 while a gene‐burden test in exome sequencing data of 32,558 Caucasian individuals suggested significant ORs of 1.7 and 1.4 63 . A similar approach on 148,508 individuals, of whom 22,080 had at least one parent with AD/dementia or AD diagnosis themselves, found a nominally significant enrichment of rare ABCA7 variants in disease, although an OR was not reported 64 . Power in this cohort to find significance may have been decreased by the proxy approach in which not all 22,080 AD‐classified individuals actually developed AD, carried risk variants or may have had parents with other types of dementia.…”