Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report.
Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P = 1.27 × 10(-9) ). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude.
Department of Psychiatry Psychotic Disorders Division, McLean Hospital, Harvard Medical School, Boston, Massachusetts; Department of Psychiatry Psychosis Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Boston, Massachusetts; Psychiatric and Neurodevelopmental Genetics Unit Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
Mei-Hua
MH
Hall
Chia-Yen
CY
Chen
Bruce M
BM
Cohen
Kevin M
KM
Spencer
Deborah L
DL
Levy
Dost
D
Öngür
Jordan W
JW
Smoller
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology*; D004594:Electrophysiology / Q000379:methods*; D058068:Endophenotypes; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D011379:Prognosis; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*
bipolar disorders; endophenotypes; event-related potentials; genowide assoication; polygentic risk score; schizophrenia