title: Genomic and network patterns of schizophrenia genetic variation in human evolutionary accelerated regions.
abstract: The population persistence of schizophrenia despite associated reductions in fitness and fecundity suggests that the genetic basis of schizophrenia has a complex evolutionary history. A recent meta-analysis of schizophrenia genome-wide association studies offers novel opportunities for assessment of the evolutionary trajectories of schizophrenia-associated loci. In this study, we hypothesize that components of the genetic architecture of schizophrenia are attributable to human lineage-specific evolution. Our results suggest that schizophrenia-associated loci enrich in genes near previously identified human accelerated regions (HARs). Specifically, we find that genes near HARs conserved in nonhuman primates (pHARs) are enriched for schizophrenia-associated loci, and that pHAR-associated schizophrenia genes are under stronger selective pressure than other schizophrenia genes and other pHAR-associated genes. We further evaluate pHAR-associated schizophrenia genes in regulatory network contexts to investigate associated molecular functions and mechanisms. We find that pHAR-associated schizophrenia genes significantly enrich in a GABA-related coexpression module that was previously found to be differentially regulated in schizophrenia affected individuals versus healthy controls. In another two independent networks constructed from gene expression profiles from prefrontal cortex samples, we find that pHAR-associated schizophrenia genes are located in more central positions and their average path lengths to the other nodes are significantly shorter than those of other schizophrenia genes. Together, our results suggest that HARs are associated with potentially important functional roles in the genetic architecture of schizophrenia.
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Ke
authors: K
authors: Xu
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors: Eric E
authors: EE
authors: Schadt
authors: Gladstone Institutes, University of California, San Francisco Institute for Human Genetics, University of California, San Francisco Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors: Katherine S
authors: KS
authors: Pollard
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY joel.dudley@mssm.edu panagiotis.roussos@mssm.edu.
authors: Panos
authors: P
authors: Roussos
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY joel.dudley@mssm.edu panagiotis.roussos@mssm.edu.
authors: Joel T
authors: JT
authors: Dudley
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D022661:RNA, Untranslated / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: C000594042:HAR1 noncoding RNA, human; D022661:RNA, Untranslated
keywords: GWAS; human accelerated evolution; networks; schizophrenia