Genetic neuropathology of obsessive psychiatric syndromes

Abstract

Anorexia nervosa (AN), bulimia nervosa (BN) and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. In addition, few, if any, studies have interrogated postmortem brain tissue for evidence of expression quantitative trait loci (eQTLs) associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single-nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a nonpsychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, for example, ED (N=15) and OCD/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and nonpsychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared with controls and OCD cases compared with controls, respectively (false discovery rate (FDR) <5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain data sets.

Figure 1

Top expression quantitative trait loci (eQTLs) of ED clinical risk variants associated with gene expression in nonpsychiatric controls (N=268). (a) The effect of SNP rs674386 on LUZP1 expression and (b) the effect of rs1503433 on CGGBP1 expression. Y axis is log2 expression relative to a reference pool, adjusted for surrogate variables, sex and race.

Figure 2

Significant differentially expressed genes for eating disorder cases compared with controls for (a) LARP6, (b) MBTPS1, (c) PVALB, and (d) SMARCD3. Note that OCD cases have expression levels between controls and ED cases at these genes. Y axis represents log2 expression, adjusted for estimated surrogate variables and sex. ED, eating disorder; OCD, obsessive-compulsive disorder.

Figure 3

Top significant diagnostic eQTLs, identified by significant interaction between genotype and diagnosis for (a) rs1017412 and the expression of STK3 and (b) rs6943628 on the expression of ST13P18. Y axis represents log2 expression, adjusted for estimated surrogate variables. eQTL, expression quantitative trait locus.