Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.
Henne HolstegeMarc HulsmanCamille CharbonnierBenjamin Grenier-BoleyOlivier QuenezDetelina GrozevaJeroen G J van RooijRebecca SimsShahzad AhmadIvana NedeljkovićPenny J NorsworthyOriol Dols-IcardoHolger HummerichAmit KawaliaPhillippe AmouyelGary W BeechamClaudine BerrJoshua C BisAnne BolandPaola BossùFemke BouwmanJose BrasDominique CampionJesse Nicholas CochranAntonio DanieleJean-François DartiguesStephanie DebetteJean-François DeleuzeNicola DenningAnita L DeStefanoLindsay A FarrerMaria Victoria FernandezNick C FoxDaniela GalimbertiFrench Exome ConsortiumJohan J P GilleYann Le GuenRita GuerreiroJonathan L HainesClive HolmesMohammad Arfan IkramM Kamran IkramIris E JansenRobert KraaijMarc LathropAfina W LemstraAlberto LleóLauren LuckcuckMarcel M A M MannensRachel MarshallEden R MartinCarlo MasulloRichard MayeuxPatrizia MecocciAlun MeggyMerel O MolKevin MorganRichard M MyersBenedetta NacmiasAdam C NajValerio NapolioniFlorence PasquierPau PastorMargaret A Pericak-VanceRachel RaybouldRichard RedonMarcel J T ReindersAnne-Claire RichardSteffi G Riedel-HellerFernando RivadeneiraStéphane RousseauNatalie S RyanSalha SaadPascual Sánchez JuanGerard D SchellenbergPhilip ScheltensJonathan M SchottDavide SeripaSudha SeshadriDaoud SieErik A SistermansSandro SorbiRosalina M L van SpaendonkGianfranco SpallettaNiccolo' TesiBetty TijmsAndre G UitterlindenSven J Van der LeePieter Jelle VisserMichael WagnerDavid WallonLi-San WangAline ZareaJordi ClarimonJohn C van SwietenMichael D GreiciusJennifer S YokoyamaCarlos CruchagaJohn HardyAlfredo RamirezSimon MeadWiesje Maria van der FlierCornelia M Van DuijnJulie WilliamsGaël NicolasCeline BellenguezJean-Charles LambertPublished in: Nature genetics (2022)
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 variants 2 . 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.
Keyphrases
- copy number
- genome wide
- early onset
- genome wide association study
- dna methylation
- cognitive decline
- late onset
- single cell
- gene expression
- risk factors
- big data
- mild cognitive impairment
- machine learning
- angiotensin ii
- climate change
- risk assessment
- transcription factor
- electronic health record
- human health
- neuropathic pain