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

The Schizophrenia Polygenic Risk Score: To What Does It Predispose in Adolescence? The initial goal of genome-wide association studies (GWASs) of psychiatric disorders was 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 These SNPs are cleaned by eliminating ones that are too rare or too highly correlated with their nearest neighbor. The PRS can be examined across a range of P value thresholds, as in the first application of this method,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, we had 1 million SNPs distributed across the genome in our training sample. We would then take the 50 000 SNPs that most significantly discriminate cases and controls and note the allele (the A, T, C, or G we all learned about in basic genetics) associated with disease risk and its effect size. We then take our target sample—in this case, the well-known 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 50 000 SNPs, determine whether they have 0, 1, or 2 of the risk alleles. That 0 to 2 score is then multiplied 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 was so large—and hence rather good at separating out true- from false-positive signals—the schizophrenia PRS had, compared with many 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 so exciting about the PRS is that, to measure it, you only need DNA (and a good training set). You do not need twins or adoptees. You do not need to interview relatives. However, 2 prominent caveats are noteworthy. First, the PRS only reflects the variation captured by the individual common SNPs used for the GWAS. The PRS will not reflect rare SNPs or variation arising from genomic abnormalities (eg, duplications or deletions). Second, the PRS is an aggregate measure of 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 from DNA and not 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) anxiety disorders, 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 PRS would have roughly a 45% increased risk for being in the top decile of negative symptoms or having 1 or more anxiety disorders. What is most interesting about the method used in this study is that it provides a new approach to understanding how the genetic risk for schizophrenia manifests 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 the schizophrenia PRS significantly predicted disorganized and negative symptoms but not positive symptoms. Of critical importance, the study by Jones et al2 was not performed in adults with schizophrenia but in a general population of adolescents. The significance of isolated psychotic symptoms in general 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 to be much more valid than questionnaire-based measures. However, their threshold was low, with only 1 confirmed symptom. Recent studies have raised questions about the specificity of isolated psychotic symptoms, suggesting that they might be a better 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 in content. Some items (“not much of a talker” and “not a very lively person”) would fit easily into an introversion scale. Others index amotivation (eg, “lacking get up and go”), whereas a few reflect more closely what clinicians would consider negative symptoms in patients with schizophrenia spectrum (eg, “neglecting appearance or personal hygiene” and “experiencing few or no emotions”). These findings can be usefully compared with an older study6 that compared dimensions of schizotypal symptoms in adult relatives of probands with schizophrenia and control individuals. In that study, negative symptoms and social dysfunction strongly distinguished relatives of probands with schizophrenia.6 Two negative symptoms—poor rapport and aloofness or coldness—map onto items from the CAPE. Regarding social dysfunction, the most strongly loading item was “general lack of motivation,” also close in content to CAPE items. In the older study, positive schizotypal symptoms, which included soft psychotic symptoms, did a much poorer job in indexing the familial liability to schizophrenia. Turning to the authors’ examination of anxiety and depressive disorders, they did not apply DSM criteria directly but rather used a computerized diagnostic algorithm and chose the quite low cutoff of at least 15% probability of clinical diagnosis. Seeing the specific anxiety disorders that were best reflected by the schizophrenia PRS would be of interest. Avoidant symptoms, such as those seen in social and school phobias, have been shown in family studies to identify relatives of probands with schizophrenia vs control individuals.6,7 The authors also outline several possible reasons for the lack of prediction of depression by the schizophrenia PRS. In summary, Jones et al2 have clarified the phenotypic effects of the genetic predisposition toward schizophrenia in adolescence. Most interestingly and consistent with several lines of prior evidence, the schizophrenia PRS predisposes toward a rather broad set of negative symptoms but not isolated psychotic symptoms. Some aspect of anxiety syndromes is also likely part of their phenotypic spectrum but not depression. We will surely see more studies using the PRS as a potentially powerful tool to clarify the phenotypic spectrum and/or developmental precursors of our major psychiatric disorders. This study represents a promissory note of more to come. Back to top Article Information Corresponding Author: Kenneth S. Kendler, MD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298 (kenneth.kendler@vcuhealth.org). Published Online: January 27, 2016. doi:10.1001/jamapsychiatry.2015.2964. Conflict of Interest Disclosures: None reported. References 1. Purcell SM, Wray NR, Stone JL, et al; International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748-752.PubMedGoogle Scholar 2. Jones HJ, Stergiakouli E, Tansey KE, et al. Phenotypic manifestation of genetic risk for schizophrenia during adolescence in the general population [published online January 27, 2016]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.3058.Google Scholar 3. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421-427.PubMedGoogle ScholarCrossref 4. Fanous AH, Zhou B, Aggen SH, et al; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms. Am J Psychiatry. 2012;169(12):1309-1317.PubMedGoogle ScholarCrossref 5. DeVylder JE, Burnette D, Yang LH. Co-occurrence of psychotic experiences and common mental health conditions across four racially and ethnically diverse population samples. Psychol Med. 2014;44(16):3503-3513.PubMedGoogle ScholarCrossref 6. Kendler KS, McGuire M, Gruenberg AM, Walsh D. Schizotypal symptoms and signs in the Roscommon Family Study: their factor structure and familial relationship with psychotic and affective disorders. Arch Gen Psychiatry. 1995;52(4):296-303.PubMedGoogle ScholarCrossref 7. Fogelson DL, Nuechterlein KH, Asarnow RA, et al. Avoidant personality disorder is a separable schizophrenia-spectrum personality disorder even when controlling for the presence of paranoid and schizotypal personality disorders: the UCLA Family Study. Schizophr Res. 2007;91(1-3):192-199.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Psychiatry American Medical Association

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

JAMA Psychiatry , Volume 73 (3) – Mar 1, 2016

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American Medical Association
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Copyright © 2016 American Medical Association. All Rights Reserved.
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2168-622X
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10.1001/jamapsychiatry.2015.2964
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Abstract

The initial goal of genome-wide association studies (GWASs) of psychiatric disorders was 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 These SNPs are cleaned by eliminating ones that are too rare or too highly correlated with their nearest neighbor. The PRS can be examined across a range of P value thresholds, as in the first application of this method,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, we had 1 million SNPs distributed across the genome in our training sample. We would then take the 50 000 SNPs that most significantly discriminate cases and controls and note the allele (the A, T, C, or G we all learned about in basic genetics) associated with disease risk and its effect size. We then take our target sample—in this case, the well-known 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 50 000 SNPs, determine whether they have 0, 1, or 2 of the risk alleles. That 0 to 2 score is then multiplied 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 was so large—and hence rather good at separating out true- from false-positive signals—the schizophrenia PRS had, compared with many 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 so exciting about the PRS is that, to measure it, you only need DNA (and a good training set). You do not need twins or adoptees. You do not need to interview relatives. However, 2 prominent caveats are noteworthy. First, the PRS only reflects the variation captured by the individual common SNPs used for the GWAS. The PRS will not reflect rare SNPs or variation arising from genomic abnormalities (eg, duplications or deletions). Second, the PRS is an aggregate measure of 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 from DNA and not 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) anxiety disorders, 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 PRS would have roughly a 45% increased risk for being in the top decile of negative symptoms or having 1 or more anxiety disorders. What is most interesting about the method used in this study is that it provides a new approach to understanding how the genetic risk for schizophrenia manifests 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 the schizophrenia PRS significantly predicted disorganized and negative symptoms but not positive symptoms. Of critical importance, the study by Jones et al2 was not performed in adults with schizophrenia but in a general population of adolescents. The significance of isolated psychotic symptoms in general 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 to be much more valid than questionnaire-based measures. However, their threshold was low, with only 1 confirmed symptom. Recent studies have raised questions about the specificity of isolated psychotic symptoms, suggesting that they might be a better 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 in content. Some items (“not much of a talker” and “not a very lively person”) would fit easily into an introversion scale. Others index amotivation (eg, “lacking get up and go”), whereas a few reflect more closely what clinicians would consider negative symptoms in patients with schizophrenia spectrum (eg, “neglecting appearance or personal hygiene” and “experiencing few or no emotions”). These findings can be usefully compared with an older study6 that compared dimensions of schizotypal symptoms in adult relatives of probands with schizophrenia and control individuals. In that study, negative symptoms and social dysfunction strongly distinguished relatives of probands with schizophrenia.6 Two negative symptoms—poor rapport and aloofness or coldness—map onto items from the CAPE. Regarding social dysfunction, the most strongly loading item was “general lack of motivation,” also close in content to CAPE items. In the older study, positive schizotypal symptoms, which included soft psychotic symptoms, did a much poorer job in indexing the familial liability to schizophrenia. Turning to the authors’ examination of anxiety and depressive disorders, they did not apply DSM criteria directly but rather used a computerized diagnostic algorithm and chose the quite low cutoff of at least 15% probability of clinical diagnosis. Seeing the specific anxiety disorders that were best reflected by the schizophrenia PRS would be of interest. Avoidant symptoms, such as those seen in social and school phobias, have been shown in family studies to identify relatives of probands with schizophrenia vs control individuals.6,7 The authors also outline several possible reasons for the lack of prediction of depression by the schizophrenia PRS. In summary, Jones et al2 have clarified the phenotypic effects of the genetic predisposition toward schizophrenia in adolescence. Most interestingly and consistent with several lines of prior evidence, the schizophrenia PRS predisposes toward a rather broad set of negative symptoms but not isolated psychotic symptoms. Some aspect of anxiety syndromes is also likely part of their phenotypic spectrum but not depression. We will surely see more studies using the PRS as a potentially powerful tool to clarify the phenotypic spectrum and/or developmental precursors of our major psychiatric disorders. This study represents a promissory note of more to come. Back to top Article Information Corresponding Author: Kenneth S. Kendler, MD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, PO Box 980126, Richmond, VA 23298 (kenneth.kendler@vcuhealth.org). Published Online: January 27, 2016. doi:10.1001/jamapsychiatry.2015.2964. Conflict of Interest Disclosures: None reported. References 1. Purcell SM, Wray NR, Stone JL, et al; International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748-752.PubMedGoogle Scholar 2. Jones HJ, Stergiakouli E, Tansey KE, et al. Phenotypic manifestation of genetic risk for schizophrenia during adolescence in the general population [published online January 27, 2016]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.3058.Google Scholar 3. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421-427.PubMedGoogle ScholarCrossref 4. Fanous AH, Zhou B, Aggen SH, et al; Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms. Am J Psychiatry. 2012;169(12):1309-1317.PubMedGoogle ScholarCrossref 5. DeVylder JE, Burnette D, Yang LH. Co-occurrence of psychotic experiences and common mental health conditions across four racially and ethnically diverse population samples. Psychol Med. 2014;44(16):3503-3513.PubMedGoogle ScholarCrossref 6. Kendler KS, McGuire M, Gruenberg AM, Walsh D. Schizotypal symptoms and signs in the Roscommon Family Study: their factor structure and familial relationship with psychotic and affective disorders. Arch Gen Psychiatry. 1995;52(4):296-303.PubMedGoogle ScholarCrossref 7. Fogelson DL, Nuechterlein KH, Asarnow RA, et al. Avoidant personality disorder is a separable schizophrenia-spectrum personality disorder even when controlling for the presence of paranoid and schizotypal personality disorders: the UCLA Family Study. Schizophr Res. 2007;91(1-3):192-199.PubMedGoogle ScholarCrossref

Journal

JAMA PsychiatryAmerican Medical Association

Published: Mar 1, 2016

Keywords: phenotype,anxiety disorders,adolescent,adolescent psychiatry,depressive disorders,genetic predisposition to disease,multifactorial inheritance,single nucleotide polymorphism,psychotic disorders,risk assessment,schizophrenia,psychiatric symptoms,polygenic hereditary disorder,prognostic factors,genetic risk,negative thoughts,genome-wide association study

References