Journal Article

Rare coding variants in Phospholipase D3 (PLD3) confer risk for Alzheimer's disease

Ryten, Mina, Skorupa, Tara, Sassi, Celeste, Turton, James, Morgan, Kevin, Scott, Erick, George-Hyslop, Peter St, Hernandez, Dena G., Lopez, Oscar L., Hardy, John, Cooper, Breanna, Cruchaga, Carlos, Benitez, Bruno A., Norton, Joanne, Demirci, F. Yesim, Forabosco, Paola, Cai, Yefei, Schmutz, Cameron, Bamne, Mikhil N., Singleton, Andy, Wang, Xingbin, Powell, John, Cairns, Nigel, Ridge, Perry G., Jeng, Amanda T., Levitch, Denise, Lupton, Michelle K., Bras, Jose, Gibbs, Raphael J., Leary, Maegan, Budde, John, Brkanac, Zoran, Rogaeva, Ekaterina, Hsu, Simon, Carrell, David, Munger, Ronald G., Lord, Jenny, Harari, Oscar, Medway, Christopher, Lorenzo-Betancor, Oswaldo, Corcoran, Christopher D., Topol, Eric, Goate, Alison M., Ganguli, Mary, Norton, Maria C., Jin, Sheng Chih, Tschanz, JoAnn T., Bertelsen, Sarah, Guerreiro, Rita, Pastor, Pau, Barber, Imelda, Morris, John C., Choi, Jiyoon, Karch, Celeste M., Braae, Anne, Kauwe, John S.K., Brown, Kristelle, Kamboh, M. Ilyas

2013

Overview

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.