Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression.

OBJECTIVE Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. METHOD The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. RESULTS The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. CONCLUSIONS This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

[1]  M. Owen,et al.  The Genetics of Schizophrenia , 2011 .

[2]  P. Joyce,et al.  Association of a functional polymorphism in the adrenomedullin gene (ADM) with response to paroxetine , 2010, The Pharmacogenomics Journal.

[3]  G. Jenkins,et al.  A Genomewide Association Study of Citalopram Response in Major Depressive Disorder , 2010, Biological Psychiatry.

[4]  K L Evans,et al.  Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder , 2009, Molecular Psychiatry.

[5]  A. Camargo,et al.  Identification of FAM46D as a novel cancer/testis antigen using EST data and serological analysis. , 2009, Genomics.

[6]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[7]  N. Craddock,et al.  Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk , 2009, Molecular Psychiatry.

[8]  Patrick F. Sullivan,et al.  A framework for interpreting genome-wide association studies of psychiatric disorders , 2009, Molecular Psychiatry.

[9]  R. Plenge.  Shared genetic risk factors for type 1 diabetes and celiac disease. , 2008, The New England journal of medicine.

[10]  Cisca Wijmenga,et al.  Shared and distinct genetic variants in type 1 diabetes and celiac disease. , 2008, The New England journal of medicine.

[11]  N. Wray,et al.  Genomewide Association for Major Depressive Disorder: A possible role for the presynaptic protein Piccolo , 2008, Molecular Psychiatry.

[12]  J. Rioux,et al.  Autoimmune diseases: insights from genome-wide association studies. , 2008, Human molecular genetics.

[13]  C. Spencer,et al.  Identification of loci associated with schizophrenia by genome-wide association and follow-up , 2008, Nature Genetics.

[14]  L. Tessarollo,et al.  Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions , 2008, Proceedings of the National Academy of Sciences.

[15]  S. Gabriel,et al.  Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder , 2008, Nature Genetics.

[16]  S. Gabriel,et al.  Whole-genome association study of bipolar disorder , 2008, Molecular Psychiatry.

[17]  Jianxin Shi,et al.  No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. , 2008, The American journal of psychiatry.

[18]  J. Lieberman,et al.  Genomewide association for schizophrenia in the CATIE study: results of stage 1 , 2008, Molecular Psychiatry.

[19]  Espen Røysamb,et al.  Heritability of bipolar spectrum disorders. Unity or heterogeneity? , 2008, Journal of affective disorders.

[20]  Elliot S. Gershon,et al.  Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis , 2008, Schizophrenia Research.

[21]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[22]  P. Zandi,et al.  Genome-wide scan of bipolar II disorder. , 2007, Bipolar disorders.

[23]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[24]  Nick Craddock,et al.  Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder. , 2006, Archives of general psychiatry.

[25]  N. Craddock,et al.  Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. , 2005, Schizophrenia bulletin.

[26]  S. Cichon,et al.  Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. , 2005, The American journal of psychiatry.

[27]  R. Weksberg,et al.  Clinical features of 78 adults with 22q11 deletion syndrome , 2005, American journal of medical genetics. Part A.

[28]  M. Daly,et al.  Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. , 2005, American journal of human genetics.

[29]  D. Brat,et al.  The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Lieberman,et al.  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. , 2005, The New England journal of medicine.

[31]  C. Vorhees,et al.  Abnormal neurodevelopment, neurosignaling and behaviour in Npas3‐deficient mice , 2005, The European journal of neuroscience.

[32]  D J Porteous,et al.  Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[33]  M. Thase,et al.  Demographic and diagnostic characteristics of the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). , 2004, Bipolar disorders.

[34]  Carol Dudley,et al.  Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[35]  D. Kupfer,et al.  Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. , 2004, Controlled clinical trials.

[36]  J. Smoller,et al.  Family, twin, and adoption studies of bipolar disorder , 2003, American journal of medical genetics. Part C, Seminars in medical genetics.

[37]  Rosanna Weksberg,et al.  The schizophrenia phenotype in 22q11 deletion syndrome. , 2003, The American journal of psychiatry.

[38]  D. Kupfer,et al.  Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD) , 2003, Biological Psychiatry.

[39]  P. Sham,et al.  The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. , 2003, Archives of general psychiatry.

[40]  D W Cox,et al.  Disruption of the neuronal PAS3 gene in a family affected with schizophrenia , 2003, Journal of medical genetics.

[41]  Peter McGuffin,et al.  A twin study of genetic relationships between psychotic symptoms. , 2002, The American journal of psychiatry.

[42]  H. Herken,et al.  Possible Role of Nitric Oxide and Adrenomedullin in Bipolar Affective Disorder , 2002, Neuropsychobiology.

[43]  D J Porteous,et al.  Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. , 2001, American journal of human genetics.

[44]  P. Sullivan,et al.  Genetic epidemiology of major depression: review and meta-analysis. , 2000, The American journal of psychiatry.

[45]  B. Gutiérrez,et al.  Increased morbid risk for schizophrenia in families of in-patients with bipolar illness , 2000, Schizophrenia Research.

[46]  F. McMahon,et al.  Bipolar II: the most common bipolar phenotype? , 1993, The American journal of psychiatry.

[47]  R. Heun,et al.  The distinction of bipolar II disorder from bipolar I and recurrent unipolar depression: results of a controlled family study , 1993, Acta psychiatrica Scandinavica.

[48]  C. Robert Cloninger,et al.  Are schizophrenia and affective disorder related? preliminary data from a family study. , 1993, The American journal of psychiatry.

[49]  N. Andreasen,et al.  Familial rates of affective disorder. A report from the National Institute of Mental Health Collaborative Study. , 1987, Archives of general psychiatry.

[50]  N. Andreasen,et al.  A Family Study of Bipolar II Disorder , 1984, British Journal of Psychiatry.

[51]  J. Nurnberger,et al.  A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. , 1982, Archives of general psychiatry.

[52]  M. Tsuang,et al.  Morbidity Risks of Schizophrenia and Affective Disorders among First Degree Relatives of Patients with Schizophrenia, Mania, Depression and Surgical Conditions , 1980, British Journal of Psychiatry.

[53]  M. Fava,et al.  Genome-wide association for major depressive disorder , 2012 .

[54]  J. Stockman,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2010 .

[55]  J. Lieberman,et al.  The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. , 2003, Schizophrenia bulletin.

[56]  E. Gershon,et al.  Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia , 2002, Molecular Psychiatry.

[57]  N. Andreasen,et al.  Bipolar II : Combine or keep separate? , 1985 .