Functional Polymorphisms in PRODH Are Associated with Risk and Protection for Schizophrenia and Fronto-Striatal Structure and Function

PRODH, encoding proline oxidase (POX), has been associated with schizophrenia through linkage, association, and the 22q11 deletion syndrome (Velo-Cardio-Facial syndrome). Here, we show in a family-based sample that functional polymorphisms in PRODH are associated with schizophrenia, with protective and risk alleles having opposite effects on POX activity. Using a multimodal imaging genetics approach, we demonstrate that haplotypes constructed from these risk and protective functional polymorphisms have dissociable correlations with structure, function, and connectivity of striatum and prefrontal cortex, impacting critical circuitry implicated in the pathophysiology of schizophrenia. Specifically, the schizophrenia risk haplotype was associated with decreased striatal volume and increased striatal-frontal functional connectivity, while the protective haplotype was associated with decreased striatal-frontal functional connectivity. Our findings suggest a role for functional genetic variation in POX on neostriatal-frontal circuits mediating risk and protection for schizophrenia

A method for determining haploid and triploid genotypes and their association with vascular phenotypes in Williams syndrome and 7q11.23 duplication syndrome

Abstract Background Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. However, within each group there is considerable interindividual variability in the degree to which these phenotypes are expressed. Though software exists to identify areas of copy number variation (CNV) from commonly-available SNP-chip data, this software does not provide non-diploid genotypes in CNV regions. Here, we describe a method for identifying haploid and triploid genotypes in CNV regions, and then, as a proof-of-concept for applying this information to explain clinical variability, we test for genotype-phenotype associations. Methods Blood samples for 25 individuals with WS and 13 individuals with Dup7 were genotyped with Illumina-HumanOmni5M SNP-chips. PennCNV and in-house code were used to make genotype calls for each SNP in the 7q11.23 locus. We tested for association between the presence of aortic arteriopathy and genotypes of the remaining (haploid in WS) or duplicated (triploid in Dup7) alleles. Results Haploid calls in the 7q11.23 region were made for 99.0% of SNPs in the WS group, and triploid calls for 98.8% of SNPs in those with Dup7. The G allele of SNP rs2528795 in the ELN gene was associated with aortic stenosis in WS participants (p < 0.0049) while the A allele of the same SNP was associated with aortic dilation in Dup7. Conclusions Commonly available SNP-chip information can be used to make haploid and triploid calls in individuals with CNVs and then to relate variability in specific genes to variability in syndromic phenotypes, as demonstrated here using aortic arteriopathy. This work sets the stage for similar genotype-phenotype analyses in CNVs where phenotypes may be more complex and/or where there is less information about genetic mechanisms

Genetic Interaction between COMT and Dysbindin Effects Prefrontal Cortex Function During a BOLD fMRI Working Memory Paradigm

Background: Previous studies show that the catechol-O-methyltransferase (COMT) gene and the dysbindin (DTNBP1) gene impact prefrontal cortical function. Variations in these genes have been individually associated with prefrontal cortex (PFC) blood oxygenation level dependent (BOLD) fMRI during the N-back working memory task. To investigate epistasis suggested by animal studies, we used the COMT Val158Met (rs4680) polymorphism to condition a DTNBP1 SNP (rs9296985) that showed such an effect across several case-control schizophrenia cohorts (Papaleo et al., in preparation). Methodology: We studied 401 healthy Caucasians with valid COMT rs4680 and DTNBP1 rs9296985 genotypes and high-quality BOLD fMRI data from the 2-Back task at 3T. There were no significant differences in demographic variables or 2-back performance measures (accuracy/reaction time) across genotype groups. To model COMTxDTNBP1 interaction, in SPM5, we used full-factorial ANOVAs with age and gender as covariates of no interest. Results: In healthy subjects, we found evidence for an epistatic interaction between COMT-rs4680 and DTNBP1-rs9296985. We found that in subjects with COMT-Val158 homozygous backgrounds, those with rs9296985 T/T alleles were more inefficient than those with rs9296985 T/C alleles in PFC, specifically BA 9 & 46, FWE p<0.05 (corrected for a small volume; punc<0.000). We did not find this interaction for COMT-Met158 homozygotes Conclusion: By specifically modeling an interaction based on COMT-Val vs. COMT-Met conditioning, we found that DTNBP1-rs9296985 increased PFC inefficiency only for individuals homozygous for COMT-Val158. Where other data suggest gene x gene effects, it may be important to combine larger samples with statistically-derived models to fully capture epistatic interactions

Additional file 1: of A method for determining haploid and triploid genotypes and their association with vascular phenotypes in Williams syndrome and 7q11.23 duplication syndrome

R script used for analyses. This file contains R code used to identify CNV genotypes and to perform association analyses with haploid genotypes. (R 4 kb