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Psychiatric genetics 12/2012; · 2.33 Impact Factor
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John M Hettema,
Bradley T Webb,
An-Yuan Guo,
Zhongming Zhao,
Brion S Maher,
Xiangning Chen,
Seon-Sook An, Cuie Sun,
Steven H Aggen,
Kenneth S Kendler,
Po-Hsiu Kuo,
Takeshi Otowa,
Jonathan Flint,
Edwin J van den Oord
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ABSTRACT: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions.
We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression).
Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing.
Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
Biological psychiatry 08/2011; 70(9):888-96. · 8.93 Impact Factor
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Xiangning Chen, Cuie Sun,
Qi Chen,
F Anthony O'Neill,
Dermot Walsh,
Ayman H Fanous,
Kodavali V Chowdari,
Vishwajit L Nimgaonkar,
Adrian Scott,
Sibylle G Schwab,
Dieter B Wildenauer,
Ronglin Che,
Wei Tang,
Yongyong Shi,
Lin He,
Xiong-Jian Luo,
Bing Su,
Todd L Edwards,
Zhongming Zhao,
Kenneth S Kendler
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ABSTRACT: Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease.
Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples.
From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.
PLoS ONE 02/2009; 4(9):e6875. · 4.09 Impact Factor
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ABSTRACT: Human anxiety disorders are complex diseases with relatively unknown etiology. Dysfunction of the Gamma-aminobutyric acid (GABA) system has been implicated in many neuropsychiatric conditions, including anxiety and depressive disorders. In this investigation, we explored four GABA receptor genes for their possible associations with genetic risk for anxiety disorders and depression.
Our study sample consisted of 589 cases and 539 controls selected from a large population-based twin registry based upon a latent genetic risk factor shared by several anxiety disorders, major depression, and neuroticism. We subjected these to a two-stage protocol, in which all candidate genetic markers were screened for association in stage 1 (N=376), the positive results of which were tested for replication in stage 2 (N=752). We analyzed data from 26 single nucleotide polymorphisms (SNPs) from four GABA receptor genes: GABRA2, GABRA3, GABRA6, and GABRG2.
Of the 26 SNPs genotyped in stage 1, we identified two markers in GABRA3 that met the threshold (P < or = .1) to be tested in stage 2. Phenotypic associations of these two markers failed to replicate in stage 2.
These findings suggest that common variation in the GABRA2, GABRA3, GABRA6, and GABRG2 genes does not play a major role in liability to anxiety spectrum disorders.
Depression and Anxiety 01/2009; 26(11):998-1003. · 4.18 Impact Factor
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ABSTRACT: FBXL21 gene encodes an F-box containing protein functioning in the SCF ubiquitin ligase complex. The role of the F-box protein is to recruit proteins designated for degradation to the ligase complex so they would be ubiquitinated. Using both family and case-control samples, we found consistent associations in and around FBXL21 gene. In the family sample (Irish study of high density schizophrenia families, ISHDSF, 1,350 subjects from 273 families), a minimal PDT P-value of 0.0011 was observed at rs31555. In the case-control sample (Irish case-control study of schizophrenia, ICCSS, 814 cases and 625 controls), significant associations were observed at two markers (rs1859427 P = 0.0197, and rs6861170 P = 0.0197). In haplotype analyses, haplotype 1-1 (C-T) of rs1859427-rs6861170 was overtransmitted in the ISHDSF (P = 0.0437) and was overrepresented in the ICCSS (P = 0.0177). For both samples, the associated alleles and haplotypes were identical. These data suggested that FBXL21 may be associated with schizophrenia in the Irish samples.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2008; 147B(7):1231-7. · 3.70 Impact Factor
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Sagiv Shifman,
Martina Johannesson,
Michal Bronstein,
Sam X Chen,
David A Collier,
Nicholas J Craddock,
Kenneth S Kendler,
Tao Li,
Michael O'Donovan,
F Anthony O'Neill,
Michael J Owen,
Dermot Walsh,
Daniel R Weinberger, Cuie Sun,
Jonathan Flint,
Ariel Darvasi
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ABSTRACT: Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.
PLoS Genetics 03/2008; 4(2):e28. · 8.69 Impact Factor
