Homeobox genes in obsessive-compulsive disorder

G. Nestadt; Y. Wang; M. A. Grados; M. 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; K. Y. Liang; F. S. Goes; B. Maher; A. E. Pulver; Y. Y. Shugart; D. Valle; J. F. Samuels; Y. C. Chang

doi:10.1002/ajmg.b.32001

Homeobox genes in obsessive-compulsive disorder

G. Nestadt, Y. Wang, M. A. Grados, M. 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, K. Y. Liang, F. S. Goes, B. MaherA. E. Pulver, Y. Y. Shugart, D. Valle, J. F. Samuels, Y. C. Chang

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	53-60
Number of pages	8
Journal	American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume	159 B
Issue number	1
DOIs	https://doi.org/10.1002/ajmg.b.32001
State	Published - Jan 2012

Keywords

Genetic association
LMX1A
MEIS2
NANOG
OCD
PBX1

ASJC Scopus subject areas

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

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Nestadt, G., Wang, Y., Grados, M. A., Riddle, M. A., Greenberg, B. D., Knowles, J. A., Fyer, A. J., Mccracken, J. T., Rauch, S. L., Murphy, D. L., Rasmussen, S. A., Cullen, B., Piacentini, J., Geller, D., Pauls, D., Bienvenu, O. J., Chen, Y., Liang, K. Y., Goes, F. S., ... Chang, Y. C. (2012). Homeobox genes in obsessive-compulsive disorder. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 159 B(1), 53-60. https://doi.org/10.1002/ajmg.b.32001

Nestadt, G, Wang, Y, Grados, MA, Riddle, MA, Greenberg, BD, Knowles, JA, Fyer, AJ, Mccracken, JT, Rauch, SL, Murphy, DL, Rasmussen, SA, Cullen, B, Piacentini, J, Geller, D, Pauls, D, Bienvenu, OJ, Chen, Y, Liang, KY, Goes, FS , Maher, B, Pulver, AE, Shugart, YY, Valle, D, Samuels, JF & Chang, YC 2012, 'Homeobox genes in obsessive-compulsive disorder', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, vol. 159 B, no. 1, pp. 53-60. https://doi.org/10.1002/ajmg.b.32001

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title = "Homeobox genes in obsessive-compulsive disorder",

abstract = "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.",

keywords = "Genetic association, LMX1A, MEIS2, NANOG, OCD, PBX1",

author = "G. Nestadt and Y. Wang and Grados, {M. A.} and Riddle, {M. A.} and Greenberg, {B. D.} and Knowles, {J. A.} and Fyer, {A. J.} and Mccracken, {J. T.} and Rauch, {S. L.} and Murphy, {D. L.} and Rasmussen, {S. A.} and B. Cullen and J. Piacentini and D. Geller and D. Pauls and Bienvenu, {O. J.} and Y. Chen and Liang, {K. Y.} and Goes, {F. S.} and B. Maher and Pulver, {A. E.} and Shugart, {Y. Y.} and D. Valle and Samuels, {J. F.} and Chang, {Y. C.}",

year = "2012",

month = jan,

doi = "10.1002/ajmg.b.32001",

language = "English (US)",

volume = "159 B",

pages = "53--60",

journal = "American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics",

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number = "1",

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T1 - Homeobox genes in obsessive-compulsive disorder

AU - Nestadt, G.

AU - Wang, Y.

AU - Grados, M. A.

AU - Riddle, M. A.

AU - Greenberg, B. D.

AU - Knowles, J. A.

AU - Fyer, A. J.

AU - Mccracken, J. T.

AU - Rauch, S. L.

AU - Murphy, D. L.

AU - Rasmussen, S. A.

AU - Cullen, B.

AU - Piacentini, J.

AU - Geller, D.

AU - Pauls, D.

AU - Bienvenu, O. J.

AU - Chen, Y.

AU - Liang, K. Y.

AU - Goes, F. S.

AU - Maher, B.

AU - Pulver, A. E.

AU - Shugart, Y. Y.

AU - Valle, D.

AU - Samuels, J. F.

AU - Chang, Y. C.

PY - 2012/1

Y1 - 2012/1

N2 - 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.

AB - 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.

KW - Genetic association

KW - LMX1A

KW - MEIS2

KW - NANOG

KW - OCD

KW - PBX1

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Homeobox genes in obsessive-compulsive disorder

Abstract

Keywords

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