Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Abstract

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

New insights on the genetic etiology of Alzheimer’s and related dementia

“…In locus 13, among the 4 genes, NDUFAF6 exhibited the highest number of hits but TP53INP1 was also of interest. In locus 21, a recent report pointing to an increased burden of rare variants in ATP8B4 in AD patients prioritizes this gene 28 . For the locus 29, we consider LILRB2 as a plausible risk gene according to bibliographical data 29,30 .…”

Penetrance estimation ofSORL1loss-of-function variants using a family-based strategy adjusted onAPOEgenotypes suggest a non-monogenic inheritance

“…However, segregation data of SORL1 variants remains very scarce, not allowing to assess their mode of inheritance. We showed that such variants are enriched in EOAD cases with a positive family history in a case-control study, with exome-wide significance 5 , and such results were subsequently extended to all AD cases with a clear effect on ages at onset [6][7][8] . Given the extreme rarity of premature termination codon-introducing variants in controls and very high odds ratios 6 , the question of the penetrance of such variants and a putative use for genetic counseling has been raised.…”

Identification of novel Alzheimer’s disease genes co-expressed withTREM2

“…There were multiple variants with ADSP.P-values < 0.05 in TREM2 (4) and RIN3 (2), two genes previously associated with AD and in ATP8B4 (3) and IL17RA (2). Neither ATP8B4 nor IL17RA were linked to AD by the AD GWAS performed to date 20,24,25 , but Holstege, et al 26 recently reported that carrying rare damaging variants in ATP8B4 is associated with AD.…”