Genetic liability in individuals at ultra-high risk of psychosis: A comparison study of 9 psychiatric traits

Abstract

Individuals at ultra-high risk (UHR) of psychosis are characterised by the emergence of attenuated psychotic symptoms and deterioration in functioning. In view of the high non-psychotic comorbidity and low rates of transition to psychosis, the specificity of the UHR status has been called into question. This study aims to (i) investigate if the UHR construct is associated with the genetic liability of schizophrenia or other psychiatric conditions; (ii) examine the ability of polygenic risk scores (PRS) to discriminate healthy controls from UHR, remission and conversion status. PRS was calculated for 210 youths (nUHR = 102, nControl = 108) recruited as part of the Longitudinal Youth at Risk Study (LYRIKS) using nine psychiatric traits derived from twelve large-scale psychiatric genome-wide association studies as discovery datasets. PRS was also examined to discriminate UHR-Healthy control status, and healthy controls from UHR remission and conversion status. Result indicated that schizophrenia PRS appears to best index the genetic liability of UHR, while trend level associations were observed for depression and cross-disorder PRS. Schizophrenia PRS discriminated healthy controls from UHR (R2 = 7.9%, p = 2.59 x 10−3, OR = 1.82), healthy controls from non-remitters (R2 = 8.1%, p = 4.90 x 10−4, OR = 1.90), and converters (R2 = 7.6%, p = 1.61 x 10−3, OR = 1.82), with modest predictive ability. A trend gradient increase in schizophrenia PRS was observed across categories. The association between schizophrenia PRS and UHR status supports the hypothesis that the schizophrenia polygenic liability indexes the risk for developing psychosis.

Is it possible to stage schizophrenia? A systematic review

“…In the premorbid phase, Lieberman et al [ 13 ] proposed that gene therapy could be a potential treatment. In this sense, although recent results from Copy Number Variants (CNV) [ 29 , 30 ] and Polygenic Risk Score (PRS) [ 31 , 32 ] support the contribution of genetics to both schizophrenia and the transition from the ultra-high-risk state to psychosis, there is still no consensus on its clinical use. On the other hand, Cornblatt [ 33 ] analyzed preliminary findings from the Hillside Recognition and Prevention (RAP) program.…”

“…A systematic review by Ribeiro-Santos, Teixeira and Vinicius [ 45 ] found that MCP-1 and IL-18 levels were associated with cognitive impairments in schizophrenia. In addition, Lim et al [ 32 ], Perkins et al [ 46 ], and He et al [ 47 ] reported PRS as a potential biomarker for early cognitive deficits or for the transition from the ultra-high-risk state to established psychosis.…”

Haptoglobin in ultra-high risk of psychosis – Findings from the longitudinal youth at risk study (LYRIKS)

“…Standard quality control procedures were performed in PLINK 1.9 to exclude single nucleotide polymorphisms (SNPs) with minor allele frequency <0.01, call rate <0.98, Hardy-Weinberg equilibrium p-value < 1e-06; and exclude individuals with mismatch between recorded and genotyped sex, and related individuals. Imputation was performed against the full 1000 genomes phase 3 reference panel and has been elaborated in an earlier study by Keane at al ( Lim et al, 2020 ).…”