2012年8月16日 訊 /生物谷BIOON/ --刊登在國際雜志Molecular Psychiatry上的兩篇研究報告，研究者揭示了引發(fā)強(qiáng)迫性障礙（OCD）和多動穢語綜合征（TS）的基因突變,，相關(guān)研究由麻省總醫(yī)院（Massachusetts General Hospital）的研究者承擔(dān),，研究者首次進(jìn)行了全基因組水平的相關(guān)聯(lián)分析（GWAS），揭示了引發(fā)這兩種疾病的基因突變,。
以前研究認(rèn)為，這兩種疾病（OCD和TS）是遺傳性的,，而且其含有共同的遺傳風(fēng)險因子。但是對于具體致病基因的識別卻是一項巨大的工作量,。目前研究者進(jìn)行這項研究來幫助我們理解這兩種疾病的潛在遺傳構(gòu)架和風(fēng)險所在,。
一種以強(qiáng)迫觀念和壓力為特點(diǎn)的焦慮性障礙嚴(yán)重影響著病人的生活質(zhì)量，OCD就是第四種常見的精神學(xué)疾病。而TS疾病是一種慢性混亂病癥,，主要特點(diǎn)為肌肉抽動和發(fā)音痙攣,，常常在幼年就開始發(fā)病，而且常常伴有OCD疾病樣的癥狀,。這兩種疾病在受感染的近親之間出現(xiàn)的風(fēng)險非常高,，但是卻有研究表明，在受感染和未感染的個體里,，并沒有發(fā)現(xiàn)特定的基因或者基因組區(qū)域和疾病的發(fā)病風(fēng)險相關(guān),。
由于很多基因都和OCD、TS的發(fā)病情況直接相關(guān),，因此研究者進(jìn)行了GWAS的研究,，其中在成百上千位個體中分析了其SNPs（單核苷酸多態(tài)性）的突變。國際OCD基金會,，包括9個國家的20個研究小組,，對1465個OCD個體、超過5000個對照以及400份OCD患者和其父母的樣品（三份樣品）進(jìn)行了480,，000個SNPs位點(diǎn)分析,。同時國際TS協(xié)會對來自1500個個體以及超過5200個對照的484，000個SNPs位點(diǎn)也進(jìn)行了相應(yīng)的分析,。
在OCD的研究結(jié)果中,，研究者發(fā)現(xiàn)了相關(guān)基因BTBD3，其和TS疾病基因非常相近,；發(fā)現(xiàn)的基因DLGAP1,，在小鼠實驗中，如果其被剔除便可以產(chǎn)生類似OCD疾病的癥狀,。在對TS疾病研究過程中,，研究者發(fā)現(xiàn)了基因COL27A1，其可以在小腦發(fā)育階段進(jìn)行表達(dá),，如果其突變可以幫助調(diào)節(jié)大腦前腦皮層的基因表達(dá),。（生物谷Bioon.com）
編譯自：Gene Variants That Increase Risk of Obsessive-Compulsive Disorder and Tourette Syndrome Identified
doi:10.1038/mp.2012.69
PMC:
PMID:
Genome-wide association study of Tourette's syndrome
J M Scharf, D Yu, C A Mathews, B M Neale, S E Stewart, J A Fagerness, P Evans, E Gamazon, C K Edlund, S K Service, A Tikhomirov, L Osiecki, C Illmann, A Pluzhnikov, A Konkashbaev, L K Davis, B Han, J Crane, P Moorjani, A T Crenshaw, M A Parkin, V I Reus, T L Lowe, M Rangel-Lugo, S Chouinard, Y Dion, S Girard, D C Cath, J H Smit, R A King, T V Fernandez, J F Leckman, K K Kidd, J R Kidd, A J Pakstis, M W State, L D Herrera, R Romero, E Fournier, P Sandor, C L Barr, N Phan, V Gross-Tsur, F Benarroch, Y Pollak, C L Budman, R D Bruun, G Erenberg, A L Naarden, P C Lee, N Weiss, B Kremeyer, G B Berrío, D D Campbell, J C Cardona Silgado, W C Ochoa, S C Mesa Restrepo, H Muller, A V Valencia Duarte, G J Lyon, M Leppert, J Morgan, R Weiss, M A Grados, K Anderson, S Davarya, H Singer, J Walkup, J Jankovic, J A Tischfield, G A Heiman, D L Gilbert, P J Hoekstra, M M Robertson, R Kurlan, C Liu, J R Gibbs, A Singleton, for the North American Brain Expression Consortium, J Hardy, for the UK Human Brain Expression Database, E Strengman, R A Ophoff, M Wagner, R Moessner, D B Mirel, D Posthuma, C Sabatti, E Eskin, D V Conti, J A Knowles, A Ruiz-Linares, G A Rouleau, S Purcell, P Heutink, B A Oostra, W M McMahon, N B Freimer, N J Cox and D L Pauls
Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.
doi:10.1038/mp.2012.85
PMC:
PMID:
Genome-wide association study of obsessive-compulsive disorder
S E Stewart, D Yu, J M Scharf, B M Neale, J A Fagerness, C A Mathews, P D Arnold, P D Evans, E R Gamazon, L Osiecki, L McGrath, S Haddad, J Crane, D Hezel, C Illman, C Mayerfeld, A Konkashbaev, C Liu, A Pluzhnikov, A Tikhomirov, C K Edlund, S L Rauch, R Moessner, P Falkai, W Maier, S Ruhrmann, H-J Grabe, L Lennertz, M Wagner, L Bellodi, M C Cavallini, M A Richter, E H Cook, J L Kennedy, D Rosenberg, D J Stein, S M J Hemmings, C Lochner, A Azzam, D A Chavira, E Fournier, H Garrido, B Sheppard, P Umaña, D L Murphy, J R Wendland, J Veenstra-VanderWeele, D Denys, R Blom, D Deforce, F Van Nieuwerburgh, H G M Westenberg, S Walitza, K Egberts, T Renner, E C Miguel, C Cappi, A G Hounie, M Conceição do Rosário, A S Sampaio, H Vallada, H Nicolini, N Lanzagorta, B Camarena, R Delorme, M Leboyer, C N Pato, M T Pato, E Voyiaziakis, P Heutink, D C Cath, D Posthuma, J H Smit, J Samuels, O J Bienvenu, B Cullen, A J Fyer, M A Grados, B D Greenberg, J T McCracken, M A Riddle, Y Wang, V Coric, J F Leckman, M Bloch, C Pittenger, V Eapen, D W Black, R A Ophoff, E Strengman, D Cusi, M Turiel, F Frau, F Macciardi, J R Gibbs, M R Cookson, A Singleton, for the North American Brain Expression Consortium, J Hardy, for the UK Brain Expression Database, A T Crenshaw, M A Parkin, D B Mirel, D V Conti, S Purcell, G Nestadt, G L Hanna, M A Jenike, J A Knowles, N Cox and D L Pauls
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469 410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case–control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case–control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10−6 and P=3.44 × 10−6), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10−8. However, when trios were meta-analyzed with the case–control samples, the P-value for this variant was 3.62 × 10−5, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio–case–control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio–case–control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
