Homeobox genes in obsessive-compulsive disorder

G. Nestadt, Youfa Wang, M. A. Grados, Mark A Riddle, B. D. Greenberg, J. A. Knowles, A. J. Fyer, J. T. Mccracken, S. L. Rauch, D. L. Murphy, S. A. Rasmussen, B. Cullen, J. Piacentini, D. Geller, D. Pauls, O. J. Bienvenu, Y. Chen, Kung-Yee Liang, F. S. Goes, B. MaherAnn E Pulver, Y. Y. Shugart, D. Valle, Jack Samuels, Y. C. Chang

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Background: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. Methods: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. Results: Three SNPs are most strongly associated with OCD: rs11854486 (P=0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR)=11.1 homozygous and 1.6 heterozygous) and rs4625687 [P=0.00007 (after adjustment=0.06); GRR=2.4] on 15q; and rs4387163 (P=0.0002 (after adjustment=0.08); GRR=1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150kb between PBX1 and LMX1A. Conclusions: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD.

Original languageEnglish (US)
Pages (from-to)53-60
Number of pages8
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume159 B
Issue number1
StatePublished - Jan 2012


  • Genetic association
  • LMX1A
  • MEIS2
  • OCD
  • PBX1

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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