title: Genetics of Schizophrenia: Historical Insights and Prevailing Evidence.
abstract: Schizophrenia's (SZ's) heritability and familial transmission have been known for several decades; however, despite the clear evidence for a genetic component, it has been very difficult to pinpoint specific causative genes. Even so genetic studies have taught us a lot, even in the pregenomic era, about the molecular underpinnings and disease-relevant pathways. Recurring themes emerged revealing the involvement of neurodevelopmental processes, glutamate regulation, and immune system differential activation in SZ etiology. The recent emergence of epigenetic studies aimed at shedding light on the biological mechanisms underlying SZ has provided another layer of information in the investigation of gene and environment interactions. However, this epigenetic insight also brings forth another layer of complexity to the (epi)genomic landscape such as interactions between genetic variants, epigenetic marks-including cross-talk between DNA methylation and histone modification processes-, gene expression regulation, and environmental influences. In this review, we seek to synthesize perspectives, including limitations and obstacles yet to overcome, from genetic and epigenetic literature on SZ through a qualitative review of risk factors and prevailing hypotheses. Encouraged by the findings of both genetic and epigenetic studies to date, as well as the continued development of new technologies to collect and interpret large-scale studies, we are left with a positive outlook for the future of elucidating the molecular genetic mechanisms underlying SZ and other complex neuropsychiatric disorders.
authors.affiliation: University of California, San Diego, La Jolla, CA, United States.
authors.forename: J
authors.initials: J
authors.lastname: van de Leemput
authors.affiliation: SUNY Upstate Medical University, Syracuse, NY, United States.
authors.forename: J L
authors.initials: JL
authors.lastname: Hess
authors.affiliation: SUNY Upstate Medical University, Syracuse, NY, United States.
authors.forename: S J
authors.initials: SJ
authors.lastname: Glatt
authors.affiliation: University of California, San Diego, La Jolla, CA, United States.
authors.forename: M T
authors.initials: MT
authors.lastname: Tsuang
mesh_terms: D019175:DNA Methylation; D004777:Environment; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D042421:Histone Code; D006801:Humans; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*
keywords: Contributing biological mechanisms; DNA methylation; Epigenetics; GWAS; Genetics; Genomic complexity; Histone modification; Neurodevelopment; Prefrontal cortex; Schizophrenia