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 2-4 kb) 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 150 kb 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.
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 2-4 kb) 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 150 kb 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.
Authors: R Zeller; A G Haramis; A Zuniga; C McGuigan; R Dono; G Davidson; S Chabanis; T Gibson Journal: Cell Tissue Res Date: 1999-04 Impact factor: 5.249
Authors: Lea K Davis; Dongmei Yu; Clare L Keenan; Eric R Gamazon; Anuar I Konkashbaev; Eske M Derks; Benjamin M Neale; Jian Yang; S Hong Lee; Patrick Evans; Cathy L Barr; Laura Bellodi; Fortu Benarroch; Gabriel Bedoya Berrio; Oscar J Bienvenu; Michael H Bloch; Rianne M Blom; Ruth D Bruun; Cathy L Budman; Beatriz Camarena; Desmond Campbell; Carolina Cappi; Julio C Cardona Silgado; Danielle C Cath; Maria C Cavallini; Denise A Chavira; Sylvain Chouinard; David V Conti; Edwin H Cook; Vladimir Coric; Bernadette A Cullen; Dieter Deforce; Richard Delorme; Yves Dion; Christopher K Edlund; Karin Egberts; Peter Falkai; Thomas V Fernandez; Patience J Gallagher; Helena Garrido; Daniel Geller; Simon L Girard; Hans J Grabe; Marco A Grados; Benjamin D Greenberg; Varda Gross-Tsur; Stephen Haddad; Gary A Heiman; Sian M J Hemmings; Ana G Hounie; Cornelia Illmann; Joseph Jankovic; Michael A Jenike; James L Kennedy; Robert A King; Barbara Kremeyer; Roger Kurlan; Nuria Lanzagorta; Marion Leboyer; James F Leckman; Leonhard Lennertz; Chunyu Liu; Christine Lochner; Thomas L Lowe; Fabio Macciardi; James T McCracken; Lauren M McGrath; Sandra C Mesa Restrepo; Rainald Moessner; Jubel Morgan; Heike Muller; Dennis L Murphy; Allan L Naarden; William Cornejo Ochoa; Roel A Ophoff; Lisa Osiecki; Andrew J Pakstis; Michele T Pato; Carlos N Pato; John Piacentini; Christopher Pittenger; Yehuda Pollak; Scott L Rauch; Tobias J Renner; Victor I Reus; Margaret A Richter; Mark A Riddle; Mary M Robertson; Roxana Romero; Maria C Rosàrio; David Rosenberg; Guy A Rouleau; Stephan Ruhrmann; Andres Ruiz-Linares; Aline S Sampaio; Jack Samuels; Paul Sandor; Brooke Sheppard; Harvey S Singer; Jan H Smit; Dan J Stein; E Strengman; Jay A Tischfield; Ana V Valencia Duarte; Homero Vallada; Filip Van Nieuwerburgh; Jeremy Veenstra-Vanderweele; Susanne Walitza; Ying Wang; Jens R Wendland; Herman G M Westenberg; Yin Yao Shugart; Euripedes C Miguel; William McMahon; Michael Wagner; Humberto Nicolini; Danielle Posthuma; Gregory L Hanna; Peter Heutink; Damiaan Denys; Paul D Arnold; Ben A Oostra; Gerald Nestadt; Nelson B Freimer; David L Pauls; Naomi R Wray; S Evelyn Stewart; Carol A Mathews; James A Knowles; Nancy J Cox; Jeremiah M Scharf Journal: PLoS Genet Date: 2013-10-24 Impact factor: 5.917
Authors: H Qin; J F Samuels; Y Wang; Y Zhu; M A Grados; M A Riddle; B D Greenberg; J A Knowles; A J Fyer; J T McCracken; D L Murphy; S A Rasmussen; B A Cullen; J Piacentini; D Geller; S E Stewart; D Pauls; O J Bienvenu; F S Goes; B Maher; A E Pulver; D Valle; C Lange; M Mattheisen; N C McLaughlin; K-Y Liang; E L Nurmi; K D Askland; G Nestadt; Y Y Shugart Journal: Mol Psychiatry Date: 2015-03-31 Impact factor: 15.992
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