Nature. 2014 Jan 23;505(7484):550-554. doi: 10.1038/nature12825. Epub 2013 Dec 11.

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

Cruchaga C^1,², Karch CM^#^1,², Jin SC^#¹, Benitez BA¹, Cai Y¹, Guerreiro R^3,⁴, Harari O¹, Norton J¹, Budde J¹, Bertelsen S¹, Jeng AT¹, Cooper B¹, Skorupa T¹, Carrell D¹, Levitch D¹, Hsu S¹, Choi J¹, Ryten M^3,⁵, Sassi C^3,⁴, Bras J³, Gibbs RJ^3,⁴, Hernandez DG^3,⁴, Lupton MK^6,⁷, Powell J⁶, Forabosco P⁸, Ridge PG⁹, Corcoran CD^10,¹¹, Tschanz JT^11,¹², Norton MC^11,^12,¹³, Munger RG^13,¹⁴, Schmutz C⁹, Leary M⁹, Demirci FY¹⁵, Bamne MN¹⁵, Wang X¹⁵, Lopez OL^16,¹⁷, Ganguli M¹⁸, Medway C¹⁹, Turton J¹⁹, Lord J¹⁹, Braae A¹⁹, Barber I¹⁹, Brown K¹⁹; Alzheimer's Research UK (ARUK) Consortium, Pastor P^20,^21,²², Lorenzo-Betancor O²⁰, Brkanac Z²³, Scott E²⁴, Topol E²⁴, Morgan K¹⁹, Rogaeva E²⁵, Singleton A⁴, Hardy J³, Kamboh MI^16,^16,¹⁸, George-Hyslop PS^25,²⁶, Cairns N^2,²⁷, Morris JC^27,^28,²⁹, Kauwe JSK⁹, Goate AM^1,^2,^28,^29,³⁰.

Author information

1: Department of Psychiatry, Washington University, St. Louis, MO, USA.
2: Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University St. Louis, MO, USA.
3: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
4: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
5: on behalf of UKBEC (UK Brain Expression Consortium).
6: Institute of Psychiatry, King's College London, London, UK.
7: Neuroimaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
8: Istituto di Genetica delle Popolazioni - CNR, Sassari, Italy.
9: Department of Biology, Brigham Young University, Provo, UT, 84602.
10: Department of Mathematics and Statistics, Utah State University, Logan, UT.
11: Center for Epidemiologic Studies, Utah State University, Logan, UT.
12: Department of Psychology, Utah State University, Logan, UT.
13: Department of Family Consumer and Human Development, Utah State University, Logan, UT.
14: Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan, UT.
15: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA.
16: Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA.
17: Department of Neurology, University of Pittsburgh, Pittsburgh, PA.
18: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.
19: Human Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, NG7 2UH, UK.
20: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
21: Department of Neurology, Clínica Universidad de Navarra, School of Medicine, University of Navarra, Pamplona, Spain.
22: CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
23: University of Washington. Seattle, WA.
24: The Scripps Research Institute, La Jolla, CA, US.
25: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto.
26: Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge.
27: Pathology and Immunology, Washington University, St. Louis, MO, USA.
28: Department of Neurology, Washington University, St. Louis, MO, USA.
29: Knight ADRC, Washington University, St. Louis, MO, USA.
30: Department of Genetics, Washington University, St. Louis, MO, USA.
#: Contributed equally

Abstract

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). 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 carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 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, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown 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 twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.