title: BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies.
abstract: Schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p<5×10(-5). Especially we detected five SNPs in the first two genes/loci strongly associated with negative symptoms of schizophrenia (P(meta-analysis)<6.22×10(-6)), which included three SNPs in the BCL9 gene: rs583583 showed the strongest association at a P(meta-analysis) of 6.00×10(-7) and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 ×10(-6)). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes.
authors: Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, Department of Psychiatry, El Paso, Texas, United States of America. chun.xu@ttuhsc.edu
authors: Chun
authors: C
authors: Xu
authors: Nagesh
authors: N
authors: Aragam
authors: Xia
authors: X
authors: Li
authors: Erika Cynthia
authors: EC
authors: Villla
authors: Liang
authors: L
authors: Wang
authors: David
authors: D
authors: Briones
authors: Leonora
authors: L
authors: Petty
authors: Yolanda
authors: Y
authors: Posada
authors: Tania Bedard
authors: TB
authors: Arana
authors: Grace
authors: G
authors: Cruz
authors: ChunXiang
authors: C
authors: Mao
authors: Cynthia
authors: C
authors: Camarillo
authors: Brenda Bin
authors: BB
authors: Su
authors: Michael A
authors: MA
authors: Escamilla
authors: KeSheng
authors: K
authors: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D014157:Transcription Factors
chemical_list: C111180:BCL9 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C402627:TMEM245 protein, human; D014157:Transcription Factors
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