PLD3 in Alzheimer's Disease: a Modest Effect as Revealed by Updated Association and Expression Analyses.

Alzheimer's disease (AD) is the most common form of dementia. Numerous genome-wide association studies (GWASs) have found several AD susceptibility common loci but with limited effect size. Recent next-generation sequencing studies of large AD pedigrees had identified phospholipase D3 (PLD3) p.V232M as the potentially functional rare variant with causal effect. However, four follow-up replication studies (Brief Communications Arising on Nature) questioned that PLD3 V232M might not be so important in AD. In this study, we re-analyzed all public-available genetic (rare and common variants) and expression data of PLD3, and screened coding variants within PLD3 in probands of 18 Han Chinese families with AD, to clarify the exact involvement of PLD3 in AD. Two closest homologues of PLD3, PLD1 and PLD2, were also analyzed to comprehensively understand the role of phospholipase D members in AD. We found that PLD3 variant V232M was associated with AD risk in overall sample sets (∼40,000 subjects) with a modest to moderate effect size (odds ratio [OR] = 1.53). Our results also showed that common variants and mRNA expression alterations of PLD2 play a role in AD genetic risk and pathology. Although we provided a systematic view of the involvement of PLD3 in AD at the genetic, mRNA expression, and protein levels, we could not define the exact causal or essential role of PLD3 rare variants in AD based on currently available data.