title: Multivariate Genetic Correlates of the Auditory Paired Stimuli-Based P2 Event-Related Potential in the Psychosis Dimension From the BSNIP Study.
abstract: OBJECTIVE
  The complex molecular etiology of psychosis in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is not well defined, presumably due to their multifactorial genetic architecture. Neurobiological correlates of psychosis can be identified through genetic associations of intermediate phenotypes such as event-related potential (ERP) from auditory paired stimulus processing (APSP). Various ERP components of APSP are heritable and aberrant in SZ, PBP and their relatives, but their multivariate genetic factors are less explored.
  
  
  METHODS
  We investigated the multivariate polygenic association of ERP from 64-sensor auditory paired stimulus data in 149 SZ, 209 PBP probands, and 99 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Multivariate association of 64-channel APSP waveforms with a subset of 16 999 single nucleotide polymorphisms (SNPs) (reduced from 1 million SNP array) was examined using parallel independent component analysis (Para-ICA). Biological pathways associated with the genes were assessed using enrichment-based analysis tools.
  
  
  RESULTS
  Para-ICA identified 2 ERP components, of which one was significantly correlated with a genetic network comprising multiple linearly coupled gene variants that explained ~4% of the ERP phenotype variance. Enrichment analysis revealed epidermal growth factor, endocannabinoid signaling, glutamatergic synapse and maltohexaose transport associated with P2 component of the N1-P2 ERP waveform. This ERP component also showed deficits in SZ and PBP.
  
  
  CONCLUSIONS
  Aberrant P2 component in psychosis was associated with gene networks regulating several fundamental biologic functions, either general or specific to nervous system development. The pathways and processes underlying the gene clusters play a crucial role in brain function, plausibly implicated in psychosis.
authors.affiliation: Olin Neuropsychiatry Research Center, Hartford Hospital, Institute of Living, Hartford, CT;
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Mokhtari
authors.affiliation: Olin Neuropsychiatry Research Center, Hartford Hospital, Institute of Living, Hartford, CT; balaji.narayanan@hhchealth.org.
authors.forename: Balaji
authors.initials: B
authors.lastname: Narayanan
authors.affiliation: Department of Psychology, University of Georgia, Athens, GA;
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Hamm
authors.affiliation: Olin Neuropsychiatry Research Center, Hartford Hospital, Institute of Living, Hartford, CT;
authors.forename: Pauline
authors.initials: P
authors.lastname: Soh
authors.affiliation: Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM; Image Analysis and MR Research Center, The Mind Research Network, Albuquerque, NM;
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.affiliation: Genetics Research Center, Hartford Hospital, Hartford, CT; Genomas Inc, Hartford, CT;
authors.forename: Gualberto
authors.initials: G
authors.lastname: Ruaño
authors.affiliation: Genetics Research Center, Hartford Hospital, Hartford, CT; Genomas Inc, Hartford, CT;
authors.forename: Mohan
authors.initials: M
authors.lastname: Kocherla
authors.affiliation: Genetics Research Center, Hartford Hospital, Hartford, CT;
authors.forename: Andreas
authors.initials: A
authors.lastname: Windemuth
authors.affiliation: Department of Psychology, University of Georgia, Athens, GA;
authors.forename: Brett A
authors.initials: BA
authors.lastname: Clementz
authors.affiliation: Department of Psychiatry, UT Southwestern Medical School, Dallas, TX;
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
authors.affiliation: Department of Psychiatry, UT Southwestern Medical School, Dallas, TX;
authors.forename: John A
authors.initials: JA
authors.lastname: Sweeney
authors.affiliation: Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA;
authors.forename: Matcheri S
authors.initials: MS
authors.lastname: Keshavan
authors.affiliation: Olin Neuropsychiatry Research Center, Hartford Hospital, Institute of Living, Hartford, CT; Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT.
authors.forename: Godfrey D
authors.initials: GD
authors.lastname: Pearlson
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology*; D005072:Evoked Potentials, Auditory / Q000502:physiology*; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics* / Q000503:physiopathology*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*
keywords: bipolar disorder; event-related potential; gene; pathway; psychosis; schizophrenia; single nucleotide polymorphism