Human Molecular Genetics Advance Access originally published online on April 30, 2007
Human Molecular Genetics 2007 16(12):1469-1477; doi:10.1093/hmg/ddm097
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Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance
1 Neurogenomics Division, The Translational Genomics Research Institute, 445 N Fifth Street, Phoenix, AZ 85004, USA, 2 Division of Psychiatry Research, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland, 3 The Banner Alzheimer’s Institute, 901 East Willetta Street, Phoenix, AZ 85006, USA, 4 Department of Psychiatry, University of Arizona, 1501 N. Campbell Avenue, PO Box 245002, Tucson, AZ 85724, USA, 5 Center for Integrative Human Physiology, University of Zurich, Winterthurerstr 190, 8057 Zurich, Switzerland and 6 Division of Molecular Psychology and Biozentrum, University of Basel, 4055 Basel, Switzerland
* To whom correspondence should be addressed. Tel: +1 6023438727; Fax: +1 6023438844; Email: dstephan{at}tgen.org
Received December 23, 2006; Revised March 15, 2007; Accepted April 11, 2007
Little is known about the genes and proteins involved in the process of human memory. To identify genetic factors related to human episodic memory performance, we conducted an ultra-high-density genome-wide screen at > 500 000 single nucleotide polymorphisms (SNPs) in a sample of normal young adults stratified for performance on an episodic recall memory test. Analysis of this data identified SNPs within the calmodulin-binding transcription activator 1 (CAMTA1) gene that were significantly associated with memory performance. A follow up study, focused on the CAMTA1 locus in an independent cohort consisting of cognitively normal young adults, singled out SNP rs4908449 with a P-value of 0.0002 as the most significant associated SNP in the region. These validated genetic findings were further supported by the identification of CAMTA1 transcript enrichment in memory-related human brain regions and through a functional magnetic resonance imaging experiment on individuals matched for memory performance that identified CAMTA1 allele-specific upregulation of medial temporal lobe brain activity in those individuals harboring the ‘at-risk’ allele for poorer memory performance. The CAMTA1 locus encodes a purported transcription factor that interfaces with the calcium-calmodulin system of the cell to alter gene expression patterns. Our validated genomic and functional biological findings described herein suggest a role for CAMTA1 in human episodic memory.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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