F195. ENRICHMENT OF PATHOGENIC VARIANTS ASSOCIATED WITH TREATABLE GENETIC DISEASES IN LARGE SCHIZOPHRENIA, BIPOLAR AND DEPRESSION COHORTS

Venuja Sriretnakumar,Joyce So,James Kennedy,Ricardo Harripaul,John Vincent

doi:10.1093/schbul/sby017.726

Abstract

BackgroundGenetic diseases are individually rare but collectively common. Many genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with regular medications. Treatment of the underlying genetic disease can cure the associated psychiatric symptoms or help regular medications work better. Discovery of rare genetic diseases in psychiatric patients would reveal specific treatment options, and give information about the chances of other family members being affected. In this study, we test the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected treatable inborn errors of metabolism (IEMs).MethodsUsing targeted next-generation sequencing, we screened schizophrenia (n=1132), bipolar (n=719) and major depressive disorder (n=195) patients for variants in genes associated with Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM) and acute intermittent porphyria (AIP), and compared the frequency of known and predicted pathogenic variants found to 123 136 samples from the gnomAD consortium.ResultsOur study is the first to explore the prevalence of NPC, WD, HOM and AIP gene variants in well-defined psychiatric cohorts. Among 2046 cases (male, n=1106; female, n=940), carrier rates of 0·93%, 0·98% and 0·20% for NPC, WD and HOM were seen, respectively. The carrier rate for NPC was marginally enriched in the SCZ cohort (1·15%) compared to general (95% CI, 0·007 – 0·021; p=0·084) and comparison (95% CI, 1·967 – 5·272; p=5·16e-05) populations. AIP affected rate of 0·29% was observed across the entire psychiatric cohort relative to the general (95% CI, 0·001 – 0·006; p=3·47e-13) and comparison (95% CI, 1·572 – 10·044; p=0·012) populations, an almost 300x enrichment in comparison to what is expected in the general population.DiscussionAn enrichment of known and predicted pathogenic variants associated with NPC and AIP was found in the psychiatric cohort, especially in SCZ patients. The results of this proof-of-principle study support that rare genetic disease variants, such as those associated with treatable IEMs, may contribute to the pathogenesis and treatment responsiveness of psychiatric disorders. Discovering genetic diseases in psychiatric patients will shift how health care is delivered to these vulnerable patients by addressing underlying conditions rather than masking symptoms with medications, and has the potential to especially help patients who don’t respond to regular psychotropic medications. Further studies screening large psychiatric cohorts for pathogenic variants in a large panel of treatable IEM genes will reveal the full impact of such disorders for psychiatric patients.

Highlights

Retinoic acid (RA) is intrinsically linked to neurodevelopment and has been implicated in schizophrenia (SZ)
We found evidence of an increased burden of rare variants within predicted DR5-retinoic acid response element (RARE) in SZ (P = 0.017, odds ratio [OR] = 1.094, 95% confidence interval [CI] = 1.023- 1.186), there was no significant difference between the cognitive subtypes (CD/cognitively spared (CS), P = 0.8, OR = 1.002, 95% CI = 0.961–1.045)
Using targeted next-generation sequencing, we screened schizophrenia (n=1132), bipolar (n=719) and major depressive disorder (n=195) patients for variants in genes associated with Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM) and acute intermittent porphyria (AIP), and compared the frequency of known and predicted pathogenic variants found to 123 136 samples from the gnomAD consortium

Summary

Background

Pathological and genetic evidence suggest that oligodendrocyte (OL) or myelin deficits are associated with schizophrenia, the contribution of OL/myelin deficits to its etiology has not been clearly dissected, because OL/myelin abnormalities may be a concomitant phenomenon during the pathogenesis of schizophrenia. Methods: Using olig ablation in OLs (olig CKO) mice, we detected myelin development status and animal behaviors under normal condition or subjected to social isolation. We examined the therapeutic effect of FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) on animal behaviors. Results: Our results demonstrated that deleting of olig leaded to impaired development of OLs and myelin deficit from postnatal day (P14) to P56, preferentially in cerebral cortex, and these young adult Olig KO mice showed anxiety-like behavior, motor skill learning deficit and cognitive deficit. Olig CKO mice exhibited earlier social avoidance behavior than the WT littermates under prolonged social isolation, indicating that myelin deficit may enhance risk of schizophrenia upon environmental stress attacking. Enhancing oligodendrocyte generation and myelin repair by quetiapine or clemastine successfully reversed the above phenotype.

Findings