Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 174; no. 8; pp. 817 - 827
• Main Authors: Kos, Mark Z., Carless, Melanie A., Peralta, Juan, Curran, Joanne E., Quillen, Ellen E., Almeida, Marcio, Blackburn, August, Blondell, Lucy, Roalf, David R., Pogue‐Geile, Michael F., Gur, Ruben C., Göring, Harald H.H., Nimgaonkar, Vishwajit L., Gur, Raquel E., Almasy, Laura
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-12-2017
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Axonogenesis; Case-Control Studies; Cognition; Epistasis; Exome; exome sequences; Family; Female; Gene expression; Genetic Markers; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Humans; Kinases; Learning; Male; Memory; Mental disorders; Mental Status and Dementia Tests; Middle Aged; Neural cell adhesion molecule; Neurocognitive Disorders - diagnosis; Neurocognitive Disorders - epidemiology; Neurocognitive Disorders - genetics; Polymorphism, Single Nucleotide; Protein interaction; Proteins; Risk Factors; Schizophrenia; Schizophrenia - complications; Schizophrenia - genetics; Single-nucleotide polymorphism; Synaptic plasticity; Young Adult; exome sequences; schizophrenia; synaptic plasticity
• ISSN: 1552-4841; 1552-485X
• DOI: 10.1002/ajmg.b.32597

Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein‐altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European‐American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non‐synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene‐based test results, protein‐protein interaction (PPI) networks, and epistatic effects. Using a significance threshold of FDR < 0.1, association was detected for rs10941112 (p = 2.1 × 10−5; q‐value = 0.073) in AMACR, a gene involved in fatty acid metabolism and previously implicated in schizophrenia, with significant cis effects on gene expression (p = 5.5 × 10−4), including brain tissue data from the Genotype‐Tissue Expression project (minimum p = 6.0 × 10−5). A second SNP, rs10378 located in TMEM176A, also shows risk effects in the exome data (p = 2.8 × 10−5; q‐value = 0.073). PPIs among our top gene‐based association results (p < 0.05; n = 359 genes) reveal significant enrichment of genes involved in NCAM‐mediated neurite outgrowth (p = 3.0 × 10−5), while exome‐wide SNP‐SNP interaction effects for rs10941112 and rs10378 indicate a potential role for kinase‐mediated signaling involved in memory and learning. In conclusion, these association results implicate AMACR and TMEM176A in schizophrenia risk, whose effects may be modulated by genes involved in synaptic plasticity and neurocognitive performance.