title: Whole brain expression of bipolar disorder associated genes: structural and genetic analyses.
abstract: Studies of bipolar disorder (BD) suggest a genetic basis of the illness that alters brain function and morphology. In recent years, a number of genetic variants associated with BD have been identified. However, little is known about the associated genes, or brain circuits that rely upon their function. Using an anatomically comprehensive survey of the human transcriptome (The Allen Brain Atlas), we mapped the expression of 58 genes with suspected involvement in BD based upon their relationship to SNPs identified in genome wide association studies (GWAS). We then conducted a meta-analysis of structural MRI studies to identify brain regions that are abnormal in BD. Of 58 BD associated genes, 22 had anatomically distinct expression patterns that could be categorized into one of three clusters (C1-C3). Brain regions with the highest and lowest expression of these genes did not overlap strongly with anatomical sites identified as abnormal by structural MRI except in the parahippocampal gyrus, the inferior/superior temporal gyrus and the cerebellar vermis, regions where overlap was significant. Using the 22 genes in C1-C3 as reference points, additional genes with correlated expression patterns were identified and organized into sets based on similarity. Further analysis revealed that five of these gene sets were significantly associated with BD, suggesting that anatomical expression profile is correlated with genetic susceptibility to BD, particularly for genes in C2. Our data suggest that expression profiles of BD-associated genes do not explain the majority of structural abnormalities observed in BD, but may be useful in identifying new candidate genes. Our results highlight the complex neuroanatomical basis of BD, and reinforce illness models that emphasize impaired brain connectivity.
authors.affiliation: Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America; Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCarthy
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Sherri
authors.initials: S
authors.lastname: Liang
authors.affiliation: Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America; Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Spadoni
authors.affiliation: Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America; Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.affiliation: Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America; Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Simmons
mesh_terms: D001271:Atlases as Topic; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping; D065814:Cerebellar Vermis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006801:Humans; D008279:Magnetic Resonance Imaging; D008959:Models, Neurological; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020534:Parahippocampal Gyrus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059467:Transcriptome
chemical_list: D009419:Nerve Tissue Proteins