The Schizophrenia Polygenic Risk Score: To What Does It Predispose in Adolescence?

The initial goal of genome-wide association studies (GWASs) ofpsychiatricdisorderswas to identify individual genetic variants that predispose to illness. Along the way, another application of GWAS data was discovered1: the polygenic risk score (PRS). The concept is simple. We start with all single-nucleotide polymorphisms (SNPs) assessed in a training sample. In this issue of JAMA Psychiatry, Jones et al2 report findings using the second Psychiatric Genomics Consortium schizophrenia GWAS as that sample.3 TheseSNPsarecleanedbyeliminatingones thatare toorare or too highly correlated with their nearest neighbor. The PRS canbeexaminedacross a rangeofPvalue thresholds, as in the first application of thismethod,1 or, as in the study by Jones et al,2 to a single a priori threshold, such as P = .05. For simplicity, imagine that, after cleaning,wehad 1million SNPs distributedacross thegenome inour training sample.Wewould then take the50000SNPs thatmost significantlydiscriminatecases and controls andnote the allele (theA, T, C, orGweall learned about in basic genetics) associatedwith disease risk and its effect size.We then takeour target sample—in this case, thewellknown Avon Longitudinal Study of Parents and Children, a population-based cohort from western England. For each individual, we examine their GWAS data and, for each of our 50000SNPs,determinewhether theyhave0, 1, or 2of the risk alleles. That 0 to 2 score is thenmultiplied by the effect size in the training sample (the logarithm of its odds ratio for schizophrenia) and summed.The total score represents an individual’s PRS for schizophrenia. In this case, because the training set wasso large—andhencerathergoodatseparatingout truefrom false-positive signals—the schizophrenia PRS had, compared withmany other applications of PRSs, a reasonable aggregate effect on adult samples, accounting for approximately 7% of schizophrenia case-control variation on the liability scale. What is soexcitingabout thePRS is that, tomeasure it, you onlyneedDNA(andagood trainingset).Youdonotneed twins or adoptees. You do not need to interview relatives. However, 2 prominent caveats are noteworthy. First, the PRS only reflects thevariationcapturedby the individual commonSNPs used for theGWAS. ThePRSwill not reflect rare SNPs or variation arising from genomic abnormalities (eg, duplications or deletions). Second, thePRS is anaggregatemeasureof risk and does not point to specific variants or any underlying biology. Conceptually, the PRS is therefore similar to the latent genetic variance that psychiatric geneticists have long estimated using twin and adoption designs. Unlike these latent measures, the PRS is assessed fromDNAandnot from resemblance between relatives. However, the PRS is not as predictive because the liability assessed using twin studies indexes all kinds of genomic variants. The PRS also does not have the methodologic concerns of twin studies (eg, equal environment assumption), although it does have several issues of its own that are beyond the scope of this review. What did Jones et al2 find? On a reasonably large sample of adolescents (3676 to 5444 participants), they tried to predict the following from their schizophrenia PRS: (1) positive psychotic experiences, (2) negative symptoms, (3) anxietydisorders, and (4) depression. They found that the schizophrenia PRS significantly predicted negative symptoms and anxiety disorders but not positive psychotic experiences or depression. The effect sizes of their 2 significant results were modest at approximately 1.2 per SD. Therefore, an individual in the top 2.5% of the schizophrenia PRSwould have roughly a 45% increased risk for being in the top decile of negative symptomsorhaving 1 ormore anxietydisorders.What ismost interesting about themethod used in this study is that it provides a new approach to understanding how the genetic risk for schizophreniamanifests itself in adolescence—a question that formed the focus of several high-risk studies of schizophrenia launched a generation or more ago. Let us first focus on the prediction of the 2 key schizophrenia dimensions of positive and negative symptoms. As Jones et al2 point out, their findings closely mirror those reported by Fanous et al4 in adult schizophrenia samples that theschizophreniaPRSsignificantlypredicteddisorganizedand negative symptomsbutnot positive symptoms.Of critical importance, the studyby Joneset al2wasnotperformed inadults with schizophrenia but in a general population of adolescents. The significanceof isolatedpsychotic symptoms ingeneral population samples remains controversial and especially so among adolescents. To their credit, Jones et al2 used an interview-based measure that attempted to confirm the veracity of the symptom,which is likely tobemuchmorevalid than questionnaire-basedmeasures.However, their thresholdwas low, with only 1 confirmed symptom. Recent studies have raised questions about the specificity of isolated psychotic symptoms, suggesting that theymightbeabetter indicator for a broad vulnerability to psychopathology rather than a specific index of schizophrenia.5 The most intriguing result in this study was the relationship between the schizophrenia PRS and negative symptoms. The negative symptom scale used (the Community Assessment of Psychic Experiences [CAPE]) is heterogeneous Related article page 221 Opinion