Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia

S G Potkin, J A Turner, J A Fallon, A Lakatos, D B Keator, G Guffanti, F Macciardi
2008 Molecular Psychiatry  
We have discovered two genes, RSRC1 and ARHGAP18, associated with schizophrenia and in an independent study provided additional support for this association. We have both discovered and verified the association of two genes, RSRC1 and ARHGAP18, with schizophrenia. We combined a genome-wide screening strategy with neuroimaging measures as the quantitative phenotype and identified the single nucleotide polymorphisms (SNPs) related to these genes as consistently associated with the phenotypic
more » ... tion. To control for the risk of false positives, the empirical Pvalue for association significance was calculated using permutation testing. The quantitative phenotype was Blood-Oxygen-Level Dependent (BOLD) Contrast activation in the left dorsal lateral prefrontal cortex measured during a working memory task. The differential distribution of SNPs associated with these two genes in cases and controls was then corroborated in a larger, independent sample of patients with schizophrenia (n = 82) and healthy controls (n = 91), thus suggesting a putative etiological function for both genes in schizophrenia. Up until now these genes have not been linked to any neuropsychiatric illness, although both genes have a function in prenatal brain development. We introduce the use of functional magnetic resonance imaging activation as a quantitative phenotype in conjunction with genome-wide association as a gene discovery tool. . Author contributions: The fMRI task, imaging data from the discovery sample and imaging analyses for these results were programmed and implemented by Jessica Turner; the neuroanatomical and neuroscience expertize and genetic annotation was contributed by James Fallon; the genetic data analysis, PLINK and Eigenstrat analyses and genetic annotation were performed by Guia Guffanti and Fabio Macciardi; the in silico annotations were performed by Anita Lakatos; the visualization and gene viewer methods were developed by David Keator; the design and oversight of the experiments and analyses were the responsibility of Steven Potkin. Article preparation was a joint effort of all authors. Supplementary Information accompanies the paper on the Molecular Psychiatry website Chromosome 3 QT (left Brodmann area 46) analysis-28 cases Case-control analysis 82 cases and 91 controls Marker Position Uncorrected P-value Empirical P-value Minor allele MAF (case) MAF (ctrl) OR (95% CI) P-value (permuted) rs6778370 Chromosome 6 QT (left Brodmann area 46) analysis-28 cases Case-control analysis 82 cases and 91 controls Marker Position Uncorrected P-value Empirical P-value Minor allele MAF (case) MAF (ctrl) OR (95%CI) P-value (permuted) rs9398913
doi:10.1038/mp.2008.127 pmid:19065146 pmcid:PMC3254586 fatcat:zov6oarjuba5biiqchbomoatsi