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Human Molecular Genetics Advance Access published online on December 12, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl445
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© The Author 2006. Published by Oxford University Press. All rights reserved

Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome

Lauren A. Weiss1,2, Shaun Purcell1,2, Skye Waggoner2, Kate Lawrence3, David Spektor3, Mark J. Daly2,4, Pamela Sklar*,1,2,5 and David Skuse3,5

1 Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School 2 Medical and Population Genetics Group, Broad Institute of MIT and Harvard 3 Behavioural and Brain Sciences Unit, Institute of Child Health, University College London 4 Department of Medicine, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School

* Correspondence: Pamela Sklar, MD PhD, Associate Professor of Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, tel: 617-726-0475, fax: 617-726-0830, sklar{at}chgr.mgh.harvard.edu

Received July 28, 2006; Revised November 21, 2006; Accepted November 21, 2006

One third of women with Turner syndrome (45, X) have autism-like social and communication difficulties, despite normal verbal IQ. Deletion mapping of the X-chromosome implicated 5 Mb of Xp11.3-4 as critical for recognition of facial fear, a quantitative measure of social cognition. Variability in fear recognition accuracy in Turner syndrome suggested the existence of a quantitative trait locus (QTL) revealed by X monosomy. We aimed to identify the gene(s) influencing fear recognition by dense mapping of the 5 Mb region. Initial regression-based association mapping of fear recognition in 93 women with Turner syndrome across the critical region was performed, using genotype data at 242 single nucleotide polymorphisms (SNPs). We identified three regions of interest, in which 52 additional SNPs were genotyped. The third region then contained four SNPs associated with fear recognition (0.0030 > P>> 0.00046). We obtained an independent sample of 77 Turner syndrome females that we genotyped for 77 SNPs in the initial regions of interest. Region three showed association in the same direction, maximal at SNPs rs7055196 and rs7887763 (P= 0.022 each). Four SNPs in strong linkage disequilibrium (LD), including this pair, span 40 kb within a novel transcript, EF-hand domain containing 2 (EFHC2). In the combined Turner syndrome samples, the most strongly associated SNP (P = 0.00007) has frequency of 8.8% and an estimated effect size accounting for over 13% of the variance in fear recognition. EFHC2 shows genealogy and extended LD consistent with directional selection. This novel QTL may influence social cognition in the general population and in autism.

5 These authors contributed equally to the manuscript.


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