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Common variants at 12q14 and 12q24 are associated with hippocampal volume
journal contribution
posted on 2023-05-17, 11:33 authored by Bis, JC, Decarli, C, Smith, AV, Van Der Lijn, F, Crivello, F, Fornage, M, Debette, S, Shulman, JM, Schmidt, H, Srikanth, V, Schuur, M, Yu, L, Choi, S-H, Sigurdsson, S, Verhaaren, BFJ, Destefano, AL, Lambert, J-C, Jack, CR, Struchalin, M, Jim StankovichJim Stankovich, Ibrahim-Verbaas, CA, Fleischman, D, Zijdenbos, A, Den Heijer, T, Mazoyer, B, Coker, LH, Enzinger, C, Danoy, P, Amin, N, Arfanakis, K, Van Buchem, MA, De Bruijn, RFAG, Beiser, A, Dufouil, C, Huang, J, Cavalieri, M, Russell Thomson, Niessen, WJ, Chibnik, LB, Gislason, GK, Hofman, A, Pikula, A, Amouyel, P, Freeman, KB, Phan, TG, Oostra, BA, Stein, JL, Medland, SE, Vasquez, AA, Hibar, DP, Wright, MJ, Franke, B, Martin, NG, Thompson, PM, Nalls, MA, Uitterlinden, AG, Au, R, Elbaz, A, Beare, RJ, Van Swieten, JC, Lopez, OL, Harris, TB, Chouraki, V, Breteler, MMB, De Jager, PL, Becker, JT, Vernooij, MW, Knopman, D, Fazekas, F, Wolf, PA, Van Der Lugt, A, Gudnason, V, Longstreth, WT, Brown, MA, Bennett, DA, Van Duijn, CM, Mosley, TH, Schmidt, R, Tzourio, C, Launer, LJ, Ikram, MA, Seshadri, SAging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of < 4.0 x 10-7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 x 10-11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 x 10-11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 x 10-7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 x 10-7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.
History
Publication title
Nature GeneticsVolume
44Issue
5Pagination
545-551ISSN
1061-4036Department/School
Menzies Institute for Medical ResearchPublisher
Nature Publishing GroupPlace of publication
United StatesRights statement
Copyright 2012 the authors.Repository Status
- Restricted
