Cumulative role of rare and common putative functional genetic variants at NPAS3 in schizophrenia susceptibility

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 168B; no. 7; pp. 528 - 535
• Main Authors: González-Peñas, Javier, Arrojo, Manuel, Paz, Eduardo, Brenlla, Julio, Páramo, Mario, Costas, Javier
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.10.2015; Wiley Subscription Services, Inc
• Subjects: Case-Control Studies; evolution; Evolution, Molecular; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genotype; Haplotypes; human accelerated elements; Humans; Male; Nerve Tissue Proteins - genetics; neurodevelopment; Neurogenesis - genetics; Polymorphism, Single Nucleotide; rare variants; Schizophrenia - genetics; SKAT; Transcription Factors - genetics; rare variants; evolution; human accelerated elements; neurodevelopment; SKAT
• ISSN: 1552-4841; 1552-485X
• DOI: 10.1002/ajmg.b.32324

Schizophrenia may be considered a human‐specific disorder arisen as a maladaptive by‐product of human‐specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human‐specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human‐specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human‐chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty‐one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome‐wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk. © 2015 Wiley Periodicals, Inc.