Cross-Disorder Genomewide Analysis of Schizophrenia, Bipolar Disorder, and Depression

Abstract

Background 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 (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). The objective of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. Method We combined GWAS data from three large effectiveness studies of SCZ (CATIE, genotyped n = 741), BPD (STEP-BD, n = 1575) and MDD (STAR*D, n= 1938) and psychiatrically-screened controls (NIMH-GI controls, n = 1204). We applied a two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups 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, p = 3.93 × 10−8), with the best-fitting model indicating that the effect is specific to bipolar II disorder. We also observed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries including variants in NPAS3 that showed pleiotropic effects across SCZ, BPD, and MDD. 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 we do not detect genomewide significant evidence of cross-disorder effects, our study provides evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrates an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

Analysis of genetic polymorphisms of brain-derived neurotrophic factor and methylenetetrahydrofolate reductase in depressed patients in a Slovak (Caucasian) population

“…Results suggest for more equivocal role of the MTHFR C677T polymorphism in conferring susceptibility to recurrent unipolar depression. Later studies on Caucasian population showed also various results (Hernandez et al 2009;Huang et al 2010). While Huang et al (2010) Peerbooms et al (2011) have examined the association between MTHFR and multiple psychiatric disorders (such as schizophrenia, bipolar disorder, and depression together) using a cross-disorder design, not separately for particular disorders and found no decisive results.…”

Adult Neurogenesis and Psychiatric Disorders

“…Another prominent risk gene for schizophrenia, NPAS3 (neuronal PAS domain-containing protein 3), was identified through linkage and association studies (Kamnasaran et al 2003;Pickard et al 2005Pickard et al , 2009Huang et al 2010). NPAS3 encodes a transcription factor of the hHLH (basic helix -loop -helix)-PAS family and is mainly expressed in the developing central nervous system and the adult brain (Brunskill et al 1999).…”

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

“…Subsequent gene-specific and genome-wide case-control association studies have linked single nucleotide polymorphisms at the NPAS3 locus with increased risk of schizophrenia (3,4), bipolar disorder (3-5) and major depression (4). Three common NPAS3 exonic variants have also been recently associated with increased risk of schizophrenia (6).…”