Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.
Holstege H., Hulsman M., Charbonnier C., Grenier-Boley B., Quenez O., Grozeva D., van Rooij JGJ., Sims R., Ahmad S., Amin N., Norsworthy PJ., Dols-Icardo O., Hummerich H., Kawalia A., Amouyel P., Beecham GW., Berr C., Bis JC., Boland A., Bossù P., Bouwman F., Bras J., Campion D., Cochran JN., Daniele A., Dartigues J-F., Debette S., Deleuze J-F., Denning N., DeStefano AL., Farrer LA., Fernández MV., Fox NC., Galimberti D., Genin E., Gille JJP., Le Guen Y., Guerreiro R., Haines JL., Holmes C., Ikram MA., Ikram MK., Jansen IE., Kraaij R., Lathrop M., Lemstra AW., Lleó A., Luckcuck L., Mannens MMAM., Marshall R., Martin ER., Masullo C., Mayeux R., Mecocci P., Meggy A., Mol MO., Morgan K., Myers RM., Nacmias B., Naj AC., Napolioni V., Pasquier F., Pastor P., Pericak-Vance MA., Raybould R., Redon R., Reinders MJT., Richard A-C., Riedel-Heller SG., Rivadeneira F., Rousseau S., Ryan NS., Saad S., Sanchez-Juan P., Schellenberg GD., Scheltens P., Schott JM., Seripa D., Seshadri S., Sie D., Sistermans EA., Sorbi S., van Spaendonk R., Spalletta G., Tesi N., Tijms B., Uitterlinden AG., van der Lee SJ., Visser PJ., Wagner M., Wallon D., Wang L-S., Zarea A., Clarimon J., van Swieten JC., Greicius MD., Yokoyama JS., Cruchaga C., Hardy J., Ramirez A., Mead S., van der Flier WM., van Duijn CM., Williams J., Nicolas G., Bellenguez C., Lambert J-C.
Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.