Common variants at 12q14 and 12q24 are associated with hippocampal volume

Joshua C. Bis, Charles DeCarli, Albert Vernon Smith, Fedde Van Der Lijn, Fabrice Crivello, Myriam Fornage, Stephanie Debette, Joshua M. Shulman, Helena Schmidt, Velandai Srikanth, Maaike Schuur, Lei Yu, Seung Hoan Choi, Sigurdur Sigurdsson, Benjamin F J Verhaaren, Anita L. Destefano, Jean Charles Lambert, Clifford R. Jack, Maksim Struchalin, Jim StankovichCarla A. Ibrahim-Verbaas, Debra Fleischman, Alex Zijdenbos, Tom Den Heijer, Bernard Mazoyer, Laura H. Coker, Christian Enzinger, Patrick Danoy, Najaf Amin, Konstantinos Arfanakis, Mark A. Van Buchem, Renée F A G De Bruijn, Alexa Beiser, Carole Dufouil, Juebin Huang, Margherita Cavalieri, Russell Thomson, Wiro J. Niessen, Lori B. Chibnik, Gauti K. Gislason, Albert Hofman, Aleksandra Pikula, Philippe Amouyel, Kevin B. Freeman, Thanh G. Phan, Ben A. Oostra, Jason L. Stein, Sarah E. Medland, Alejandro Arias Vasquez, Derrek P. Hibar, Margaret J. Wright, Barbara Franke, Nicholas G. Martin, Paul M. Thompson, Michael A. Nalls, Andre G. Uitterlinden, Rhoda Au, Alexis Elbaz, Richard J. Beare, John C. Van Swieten, Oscar L. Lopez, Tamara B. Harris, Vincent Chouraki, Monique M B Breteler, Philip L. De Jager, James T. Becker, Meike W. Vernooij, David Knopman, Franz Fazekas, Philip A. Wolf, Aad Van Der Lugt, Vilmundur Gudnason, W. T. Longstreth, Matthew A. Brown, David A. Bennett, Cornelia M. Van Duijn, Thomas H. Mosley, Reinhold Schmidt, Christophe Tzourio, Lenore J. Launer, M. Arfan Ikram, Sudha Seshadri

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

Aging 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 × 10 -7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 -11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 -11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 -7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 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.

Original languageEnglish (US)
Pages (from-to)545-551
Number of pages7
JournalNature Genetics
Volume44
Issue number5
DOIs
StatePublished - May 2012

ASJC Scopus subject areas

  • Genetics

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    Bis, J. C., DeCarli, C., Smith, A. V., Van Der Lijn, F., Crivello, F., Fornage, M., Debette, S., Shulman, J. M., Schmidt, H., Srikanth, V., Schuur, M., Yu, L., Choi, S. H., Sigurdsson, S., Verhaaren, B. F. J., Destefano, A. L., Lambert, J. C., Jack, C. R., Struchalin, M., ... Seshadri, S. (2012). Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics, 44(5), 545-551. https://doi.org/10.1038/ng.2237