Identification of common variants associated with human hippocampal and intracranial volumes

Jason L. Stein, Sarah E. Medland, Alejandro Arias Vasquez, Derrek P. Hibar, Rudy E. Senstad, Anderson M. Winkler, Roberto Toro, Katja Appel, Richard Bartecek, Orjan Bergmann, Manon Bernard, Andrew A. Brown, Dara M. Cannon, M. Mallar Chakravarty, Andrea Christoforou, Martin Domin, Oliver Grimm, Marisa Hollinshead, Avram J. Holmes, Georg HomuthJouke-Jan Hottenga, Camilla Langan, Lorna M. Lopez, Narelle K. Hansell, Kristy S. Hwang, Sungeun Kim, Gonzalo Laje, Phil H. Lee, Xinmin Liu, Eva Loth, Anbarasu Lourdusamy, Morten Mattingsdal, Sebastian Mohnke, Susana Munoz Maniega, Kwangsik Nho, Allison C. Nugent, Carol O'Brien, Martina Papmeyer, Benno Putz, Adaikalavan Ramasamy, Jerod Rasmussen, Mark Rijpkema, Shannon L. Risacher, J. Cooper Roddey, Marie-Jose van Tol, Andre Aleman, Martijn Van den Heuvel, Dick J. Veltman, Albert V. Smith, Giovanni Coppola, ADNI, EpiGen Consortium, IMAGEN Consortium, Saguenay Youth Study Grp SYS, Cohorts Heart Aging Res Genomic Ep, Enhancing Neuro Imaging Genetics M

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Abstract

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease(1,2) and is reduced in schizophrenia(3), major depression(4) and mesial temporal lobe epilepsy(5). Whereas many brain imaging phenotypes are highly heritable(6,7), identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 x 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 x 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)).

Original languageEnglish
Pages (from-to)552-+
Number of pages12
JournalNature Genetics
Volume44
Issue number5
DOIs
Publication statusPublished - May-2012

Keywords

  • GENOME-WIDE ASSOCIATION
  • TEMPORAL-LOBE EPILEPSY
  • AUTOMATED SEGMENTATION
  • GENOTYPE IMPUTATION
  • ALZHEIMERS-DISEASE
  • BRAIN VOLUME
  • HUMAN HEIGHT
  • FUNCTIONAL IMPLICATIONS
  • NA+/H+ EXCHANGER
  • UNIFIED APPROACH

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