title: Neurophysiologic effect of GWAS derived schizophrenia and bipolar risk variants.
abstract: Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) as disease associated variants for schizophrenia (SCZ), bipolar disorder (BPD), or both. Although these results are statistically robust, the functional effects of these variants and their role in the pathophysiology of SCZ or BPD remain unclear. Dissecting the effects of risk genes on distinct domains of brain function can provide important biological insights into the mechanisms by which these genes may confer illness risk. This study used quantitative event related potentials to characterize the neurophysiological effects of well-documented GWAS-derived SCZ/BPD susceptibility variants in order to map gene effects onto important domains of brain function. We genotyped 199 patients with DSM-IV diagnoses of SCZ or BPD and 74 healthy control subjects for 19 risk SNPs derived from previous GWAS findings and tested their association with five neurophysiologic traits (P3 amplitude, P3 latency, N1 amplitude, P2 amplitude, and P50 sensory gating responses) known to be abnormal in psychosis. The TCF4 SNP rs17512836 risk allele showed a significant association with reduced auditory P3 amplitude (P = 0.00016) after correction for multiple testing. The same allele was also associated with delayed P3 latency (P = 0.005). Our results suggest that a SCZ risk variant in TCF4 is associated with neurophysiologic traits thought to index attention and working memory abnormalities in psychotic disorders. These findings suggest a mechanism by which TCF4 may contribute to the neurobiological basis of psychotic illness.
authors: Psychotic Disorders Division, Department of Psychiatry, McLean Hospital, Harvard Medical School, Boston, Massachusetts; Department of Psychiatry, Psychology Research Laboratory, McLean Hospital, Harvard Medical School, Boston, Massachusetts; Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
authors: Mei-Hua
authors: MH
authors: Hall
authors: Deborah L
authors: DL
authors: Levy
authors: Dean F
authors: DF
authors: Salisbury
authors: Steve
authors: S
authors: Haddad
authors: Patience
authors: P
authors: Gallagher
authors: Mary
authors: M
authors: Lohan
authors: Bruce
authors: B
authors: Cohen
authors: Dost
authors: D
authors: Ongür
authors: Jordan W
authors: JW
authors: Smoller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D058256:Brain Waves; D004569:Electroencephalography; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005819:Genetic Markers; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors
keywords: ERP; TCF4; genetics; neurophysiology; psychosis