Psychiatry and Psychology Commons^™

Network-Assisted Investigation Of Combined Causal Signals From Genome-Wide Association Studies In Schizophrenia, Peilin Jia, Lily Wang, Ayman H. Fanous, Carlos N. Pato, Todd L. Edwards, Zhongming Zhao

Psychiatry Publications

With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each …

Variants Located Upstream Of Chrnb4 On Chromosome 15q25.1 Are Associated With Age At Onset Of Daily Smoking And Habitual Smoking, Manav Kapoor, Jen-Chyong Wang, Sarah Bertelsen, Kathy Bucholz, John P. Budde, Anthony Hinrichs, Arpana Agrawal, Andrew Brooks, David Chorlian, Danielle Dick, Victor Hesselbrock, Tatiana Foroud, John Kramer, Sammuel Kuperman, Niklas Manz, John Numberger Jr, Bernice Porjesz, John Rice, Jay Tischfield, Xiaoling Xuei, Marc Schuckit, Haward J. Edenberg, Laura J. Bierut, Alison M. Goate

Psychiatry Publications

Several genome-wide association and candidate gene studies have linked chromosome 15q24–q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking theCHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were …

The Interleukin 3 Gene (Il3) Contributes To Human Brain Volume Variation By Regulating Proliferation And Survival Of Neural Progenitors, Xiao-Jian Luo, Ming Li, Liang Huang, Khwangsik Nho, Min Deng, Qiang Chen, Daniel R. Weinberger, Alejandro A. Vasquez, Mark Rijpkema, Venkata S. Mattay, Andrew J. Saykin, Li Shen, Guillen Fernandez, Barbara Franke, Jing-Chun Chen, Xiang-Ning Chen, Jin-Kai Wang, Xiao Xiao, Xue-Bin Qi, Kun Xiang, Ying-Mei Peng, Xiang-Yu Cao, Yi Li, Xiao-Dong Shi, Lin Gan, Bing Su

Psychiatry Publications

One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which …

Acsl6 Is Associated With The Number Of Cigarettes Smoked And Its Expression Is Altered By Chronic Nicotine Exposure, Jingchun Chen, Darlene H. Brunzell, Kia J. Jackson, Andrew Van Der Vaart, Jennie Z. Ma, Thomas J. Payne, Richard Sherva, Lindsay A. Farrer, Pablo Gejman, Douglas F. Levinson, Peter Holmans, Steven H. Aggen, Imad Damaj, Po-Hsiu Kuo, Bradley T. Webb, Raymond Anton, Henry R. Kranzler, Joel Gelemter, Minf D. Li, Kenneth S. Kendler, Xiangning Chen

Psychiatry Publications

Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured …

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene Grin2a As A Parkinson's Disease Modifier Gene Via Interaction With Coffee, Taye H. Hamza, Honglei Chen, Erin M. Hill-Burns, Shannon L. Rhodes, Jennifer Montimurro, Denise M. Kay, Albert Tenesa, Victoria I. Kusel, Patricia Sheehan, Muthukrishnan Eaaswarkhanth, Dora Yearout, Ali Samii, John W. Roberts, Pinky Agarwal, Yvette Bordelon, Yikyung Park, Liyong Wang, Jianjun Gao, Jeffery M. Vance, Kenneth S. Kendler, Silviu-Alin Bacanu, William K. Scott, Beate Ritz, John Nutt, Stweart A. Factor, Cyrus P. Zabetian, Haydeh Payami

Psychiatry Publications

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the …

Schizophrenia Gene Networks And Pathways And Their Applications For Novel Candidate Gene Selection, Jingchun Sun, Peilin Jia, Ayman H. Fanous, Edwin Van Den Oord, Xiangning Chen, Brien P. Riley, Richard L. Amdur, Kenneth S. Kendler, Zhongming Zhao

Psychiatry Publications

Background

Schizophrenia (SZ) is a heritable, complex mental disorder. We have seen limited success in finding causal genes for schizophrenia from numerous conventional studies. Protein interaction network and pathway-based analysis may provide us an alternative and effective approach to investigating the molecular mechanisms of schizophrenia.

Methodology/Principal Findings

We selected a list of schizophrenia candidate genes (SZGenes) using a multi-dimensional evidence-based approach. The global network properties of proteins encoded by these SZGenes were explored in the context of the human protein interactome while local network properties were investigated by comparing SZ-specific and cancer-specific networks that were extracted from the human interactome. …

Multiple Independent Loci At Chromosome 15q25.1 Affect Smoking Quantity: A Meta-Analysis And Comparison With Lung Cancer And Copd, Nancy L. Saccone, Robert C. Culverhouse, Tae-Hwi Schwantes-An, Dale S. Cannon, Xiangning Chen, Sven Cichon, Ina Giegling, Shizhong Han, Younghun Han, Kaisu Keskitalo-Vuokko, Xiangyang Kong, Maria T. Landi, Jennie Z. Ma, Susan E. Short, Sarah H. Stephens, Victoria L. Stevens, Lingwei Sun, Yufei Wang, Angela S. Wenzlaff, Steven H. Aggen, Naomi Breslau, Peter Broderick, Nilanjan Chatterjee, Jingchun Chen, Andrew C. Heath, Marku Heliovaara, Nicole R. Hoft, David J. Hunter, Majken K. Jensen, Nicholas G. Martin, Grant W. Montgomery, Tianhua Niu, Thomas J. Payne, Leena Peltonen, Michele L. Pergadia, John P. Rice, Richard Sherva, Margaret R. Spitz, Juzhong Sun, Jen C. Wang, Robert B. Weiss, William Wheeler, Stephanie H. Witt, Bao-Zhu Yang, Neil E. Caporaso, Marissa A. Ehringer, Tim Eisen, Susan M. Gapstur, Joel Gelemter, Richard Houlston, Jaakko Kaprio, Kenneth S. Kendler, Peter Kraft, Mark F. Leppert, Ming D. Li, Pamela A. F. Madden, Markus M. Nothen, Sreekumar Pillai, Marcella Rietschel, Dan Rujescu, Ann Schwartz, Christopher I. Amos, Laura J. Bierut

Psychiatry Publications

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary …

New Genomic Structure For Prostate Cancer Specific Gene Pca3 Within Bmcc1: Implications For Prostate Cancer Detection And Progression, Raymond A. Clarke, Zhongming Zhao, An-Yuan Guo, Kathrein Roper, Linda Teng, Zhi-Ming Fang, Hema Samaratunga, Martin F. Lavin, Robert A. Gardiner

Psychiatry Publications

Background

The prostate cancer antigen 3 (PCA3/DD3) gene is a highly specific biomarker upregulated in prostate cancer (PCa). In order to understand the importance of PCA3 in PCa we investigated the organization and evolution of the PCA3 gene locus.

Methods/Principal Findings

We have employed cDNA synthesis, RTPCR and DNA sequencing to identify 4 new transcription start sites, 4 polyadenylation sites and 2 new differentially spliced exons in an extended form of PCA3. Primers designed from these novel PCA3 exons greatly improve RT-PCR based discrimination between PCa, PCa metastases and BPH specimens. Comparative genomic analyses demonstrated that PCA3 has …

Genome-Wide Association Identifies A Common Variant In The Reelin Gene That Increases The Risk Of Schizophrenia Only In Women, Sagiv Shifman, Martina Johannesson, Michal Bronstein, Sam X. Chen, David A. Collier, Nicholas J. Craddock, Kenneth S. Kendler, Tao Li, Michael C. O'Donovan, F. Anthony O'Neill, Michael J. Owen, Dermot Walsh, Daniel R. Weinberger, Cuie Sun, Jonathan Flint, Ariel Darvasi

Psychiatry Publications

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 × 10−5 in women), with a significant gene-sex effect (p = 1.8 × 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 × 10−3 in …

Response, Remission & Recovery: Need To Review Outcome Measures For Schizophrenia, Amresh Shrivastava, Nilesh Shah

Psychiatry Publications

Schizophrenia is a complex neurobehavioral disorder known to be associated with poor outcome. It causes significant disability in patients and burden of care amongst relatives. Outcome in developing countries has been reported to be far better than western world, which has come into scientific scanner recently. Wide gap exists between expectations of outcome amongst patients, relatives, caregivers and professionals, which is possibly because of limitations in measurements tools. Significant number of patients remain marginalized without improvement in social & occupational functioning preventing their integration into mainstream of society despite 'clinically reported good outcome' and significant advancement in treatments. The contemporary …

Linkage Analysis Of A Model Quantitative Trait In Humans: Finger Ridge Count Shows Significant Multivariate Linkage To 5q14.1, Sarah E. Medland, Danuta Z. Loesch, Bogdan Mdzewski, Gu Zhu, Grant W. Montgomery, Nicholas G. Martin

Psychiatry Publications

The finger ridge count (a measure of pattern size) is one of the most heritable complex traits studied in humans and has been considered a model human polygenic trait in quantitative genetic analysis. Here, we report the results of the first genome-wide linkage scan for finger ridge count in a sample of 2,114 offspring from 922 nuclear families. Both univariate linkage to the absolute ridge count (a sum of all the ridge counts on all ten fingers), and multivariate linkage analyses of the counts on individual fingers, were conducted. The multivariate analyses yielded significant linkage to 5q14.1 (Logarithm of odds …