Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease

Abstract

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits.

Alzheimer’s Disease Risk Genes and Lipid Regulators

“…Overexpression of PLD3 decreased levels of ␤APP, A␤ 42 , and A␤ 40 , whereas PLD3 knockdown increased extracellular A␤ 42 and A␤ 40 [140]. Another study reported that PLD3 was expressed at significantly lower levels in neurons from AD brains compared with non-AD brains [141].…”

“…A third PLD isoform, PLD3, has been recently associated with AD through identification of PLD3 risk variants by whole-exome sequencing and functional studies [140]. Overexpression of PLD3 decreased levels of ␤APP, A␤ 42 , and A␤ 40 , whereas PLD3 knockdown increased extracellular A␤ 42 and A␤ 40 [140].…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…3 ). More specifi cally, Val232Met, a putative lossof-function polymorphism, is proposed to increase pathogenic amyloid peptide (A ␤ ) secretion and, hence, increase the risk for late-onset AD ( 81 ). This increased risk is independent of the APOE genotype ( 81 ).…”

“…More specifi cally, Val232Met, a putative lossof-function polymorphism, is proposed to increase pathogenic amyloid peptide (A ␤ ) secretion and, hence, increase the risk for late-onset AD ( 81 ). This increased risk is independent of the APOE genotype ( 81 ). Similarly, PLD3 putative loss-of-function polymorphisms have been reported to correlate with increased risk of AD in African Americans ( 81 ).…”

“…PLD1, PLD2, and PLD3 have all been implicated in AD ( 69,80,81 ). PLD3 is highly expressed in the brain, including in, but not limited to, mature neurons of the forebrain, hippocampus, and cortex (81)(82)(83). Rare coding variants in PLD3 have been associated with up to 9% of late-onset AD in 14 families of European ancestry ( 81 ) ( Fig.…”