The purine metabolism in mental illnesses: the role of the cancer gene fhit across psychiatric diseases

The fragile histidine triad (FHIT) contains a chromosomal fragile site (FRA3B) responsible for rearrangements associated with various cancers. A recent pan-cancer whole genome sequencing study revealed homozygous deletions of FHIT as one of the most significant genetic signature in metastatic cancers (Priestley et al, 2019). We found a rare deletion in the first coding exon of FHIT segregating in a sib-pair with autism spectrum disorder (ASD). FHIT is involved in the biosynthesis of adenine nucleotides (ATP, ADP and AMP) released in the synaptic area, activating the purinergic G protein-coupled receptors P2X and P2Y of postsynaptic neurons. Considering its role in brain and the observed comorbidity rate between psychiatric diseases and cancer, we conducted a comprehensive genetic study of FHIT to establish its genetic relationship between these conditions. We performed a gene-based association test for common variants (> 6,000 SNPs) of FHIT using GWAS data of 10 psychiatric conditions via MAGMA, as well as for 7 cancer phenotypes. A meta-analysis was performed using the weighted Stouffer's Z method for psychiatric diseases and cancers, respectively. Sequencing projects such as SCHEMA (schizophrenia, SCZ), ASC (ASD), and BipEx (bipolar disorder, BD) were used to assess the role of rare variants. A copy number variant (CNV) study was performed combining previous studies in psychiatry and gnomAD population data as reference (11,413 cases; 14,317 controls). Gene expression analysis of FHIT was assessed in BD and SCZ using brain RNAseq data (PsychENCODE project: 73 BD, 95 SCZ, 259 controls). Protein quantification of frontal cortex (BA9/BA46) specimens was performed within SCZ individuals (n=23) and matched controls (n=21) via western blot. We found gene-based association of FHIT with SCZ (P=1.2E-12), major depressive disorder (MDD; P=4.5E-07), ADHD (P=0.004), and BD (P=0.004). Meta-analysis suggested a role for FHIT across psychiatric disorders (P=2.2E-14). Conversely, no significant association was observed for any of the cancer phenotypes, nor in the combined clinical group. The structural variant analysis found association between rare CNVs on FHIT and psychiatric disorders (adjP=0.031), with higher impact for deletions (P=4E-4), especially those encompassing the first coding exon in ASD. No rare variants burden of FHIT was observed from sequencing projects in SCZ, BD and ASD. No difference was observed for FHIT in transcript or protein level in brains of SCZ or BD patients. We found a pleiotropic role of FHIT across psychiatric disorders mediated by different genetic variation. Common variants implicated in SCZ, BD and MDD were mostly found at 5’ region of the gene probably acting on its regulation. Despite rare, CNVs in FHIT increase risk for psychiatric susceptibility, especially deletions in ASD. However, gene expression analysis or protein quantification from brain tissues of SCZ and BD patients did not endorse the genetic findings, probably due to limited sample power. FHIT is highly expressed in brain tissues, and its dysregulation may affect the homeostasis of precursors for ATP or adenosine, which have roles as neurotransmitter and neuromodulator in the synaptic space. While homozygous deletions of this gene seem to be related to tumour progression, its role in psychiatric diseases via common risk alleles and heterozygous deletions may dysregulate the first steps of the metabolic pathway for the biosynthesis of synaptic neurotransmission.