File Name: common polygenic variation contributes to risk of schizophrenia and bipolar disorder .zip
This is an open access article distributed under the terms of Creative Commons Attribution License. Schizophrenia is a common yet devastating mental disorder characterized by a series of cognitive, behavioral and emotional dysfunctions, none of which are pathognomonic for the disease. It includes both positive symptoms, mainly represented by hallucinations and delusions and negative ones, such as blunted affect, avolition and social isolation, along with disturbed attention, executive function and working memory 1.
Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder.
Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population.
Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores PRS , as well as specific single nucleotide polymorphisms SNPs previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences.
Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further.
The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed. This is an open-access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. The notion of the psychosis continuum postulates that psychosis is a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder are its extreme manifestations  see also .
Clinical psychotic symptoms include but are not limited to hallucinations, delusions, cognitive disorganisation, avolition and anhedonia  and can be measured in the general population . Some evidence suggests that early psychotic experiences are a risk marker for later development of a psychotic disorder  ,  , although most individuals with psychotic experiences in adolescence do not go on to develop psychotic disorders.
High scores on psychotic experiences in childhood age 11 were shown to be an indication of an increased risk of developing a psychotic disorder later in life age 26 .
In a study conducted by Kelleher et al. In contrast to this, the predictive power of these psychotic experiences for a number of psychiatric disorders strengthened with an increase in age. These findings highlight the potential value of studying psychotic experiences in mid-adolescence. A number of studies have shown that, consistent with adult schizophrenia, psychotic experiences in adolescence show a multidimensional factorial structure  — .
Although the number and content of the reported dimensions varies across studies due to the measures and statistical analyses used, most report at the very least three dimensions of Positive, Negative and Disorganisation.
Ronald et al. Findings from twin studies suggest that heritabilities of psychotic disorders are higher than for adolescent psychotic experiences. Common genetic variants have been shown to play an important role in the aetiology of both disorders . GWAS that investigate common single nucleotide polymorphisms SNPs have identified several SNPs in genic and non-genic regions that associate with schizophrenia risk reviewed in . A different approach is to use a polygenic risk score PRS , which aggregates genome-wide individual SNPs into a single score.
PRS can be used as predictors of phenotypes in other samples. In terms of the genetic relationship between adolescent psychotic experiences and adult psychotic disorders, currently the genetic correlation the degree of overlapping genetic influences between adolescent psychotic experiences and clinical psychosis remains unknown.
Here we hypothesise that if genes influencing risk for liability to psychosis are common in the general population, and if schizophrenia and bipolar disorder lie on a phenotypic continuum with psychotic experiences assessed dimensionally, schizophrenia and bipolar disorder identified genetic risk variants will also be associated with psychotic experiences.
Derks et al. The authors identified a five-dimensional structure of psychosis but found no significant correlation between any dimension and the schizophrenia PRS, after accounting for case-control status. In contrast to this, Fanous et al.
To date, one study has explored the association between psychotic experiences in the general population and schizophrenia associated genetic risk variants . Psychotic experiences were assessed as a single categorical construct, where presence of psychotic experiences was defined as presence of any one of a number of different positive psychotic experiences. The respective odds ratio per standard deviation increase in score was 1. The present study adds to this recent work by using both the schizophrenia and bipolar disorder PRS and testing for their predictiveness with quantitatively-measured specific psychotic experiences.
The present study includes separate scales for different types of positive psychotic experiences paranoia, hallucinations, grandiosity and delusion , as well as including cognitive disorganisation and negative psychotic experiences, which has not been done before.
The measures were quantitative and therefore captured varying severity of manifestation of psychotic experiences across the population. For example, paranoia was assessed in terms of how frequently individuals had paranoid thoughts and items ranged in severity from mild suspicions that others have an interest in the person all the way to fears of conspiracies.
In Approach 1 , estimates of variance explained in dimension-specific psychotic experiences in adolescence using schizophrenia and bipolar disorder PRS s were derived. For both the schizophrenia PRS and the bipolar disorder PRS, we hypothesised that the PRS would be separately associated with each of the six dimensions of psychotic experiences.
We further hypothesised that the associations would be positive. It was expected that the PRS scores would explain a smaller but significant proportion of variance in adolescent psychotic experiences than they did for the liability to schizophrenia and bipolar disorder. For each dimension of psychotic experiences in adolescence, we hypothesised that the selected risk variants would also be associated with that dimension; we regarded these as separate hypotheses to be tested individually, without adjustment for multiplicity.
It was expected that while some associations would be specific to certain dimensions and others would show pleiotropic effects i. In Approach 3 , a composite schizophrenia SNP score made up of the selected SNPs from Approach 2 was created to estimate the variance explained in quantitative dimension-specific psychotic experiences in adolescence.
It was hypothesised that the composite schizophrenia SNP score would be a significant predictor of quantitative dimension-specific psychotic experiences in adolescence and that it would explain a small proportion of variance. Finally, significant findings from Approaches 2 and 3 were tested for replication in an independent population-based sample of adolescents as used in .
TEDS is a longitudinal general population sample of twins born in England and Wales between and . TEDS originally recruited 13, families, who responded with a written consent form. The current study forms part of the Longitudinal Experiences And Perceptions LEAP project, which investigates the aetiology of psychotic experiences in adolescence. For the purposes of this study families were not contacted if they had withdrawn from TEDS, had never returned any data or had known address problems.
Of those, 5, Participants were excluded based on lack of consent at first contact or for the present study, presence of severe medical disorder s including autism spectrum disorder, lack of zygosity information or experience of severe perinatal complications. In total, 3, samples were successfully hybridized to AffymetrixGeneChip 6.
The final sample of 3, individuals comprised 1, males and 1, females. Phenotypic data on psychotic experiences was available for 2, of the 3, genotyped individuals and limited to those who were unrelated and of white background. When the oldest children of the 14, pregnancies were 7 years old additional pregnancies that failed to enrol at first attempt were added. This resulted in a total sample size of 15, pregnancies 15, fetuses.
Of the 15, fetuses, 14, were live births and 14, were alive at 1 year of age. Of the genotyped individuals, some were excluded based on one or more of the following parameters: incorrect gender assignments 61 , minimal or excessive heterozygosity , disproportionate levels of individual missingness 15 , evidence of cryptic relatedness , and non-European ancestry . The resulting sample comprised 8, genotyped individuals.
Genotypic data was available for 3, of those individuals and limited to unrelated individuals of European ancestry. Informed written consent was obtained for both studies.
SPEQ was based on existing measures that were adapted specifically for use with adolescents. Items were placed into separate subscales based on the results of principal component analysis . Paranoia subscale comprised 15 items rated on a 6-point scale not at all; rarely; once a month; once a week; several times a week; daily and the total scale ranged from 0 to Hallucinations subscale of SPEQ comprised nine items measured on a 6-point scale not at all; rarely; once a month; several times a week; once a week; daily and the total scale ranged from 0 to Grandiosity subscale consisted of eight items measured on a 4-point scale not at all; somewhat; a great deal; completely and the total scale ranged from 0 to Anhedonia subscale consisted of items asking about hedonia rated on a 6-point scale very false for me; moderately false for me; slightly false for me; slightly true for me; moderately true for me; very true for me and the total scale ranged from 0 to Anhedonia scale was reversed so that higher scores signified more Anhedonia.
Finally, Parent-reported Negative Symptoms subscale was made up of items rated on a 4-point scale not at all true; somewhat true; mainly true; definitely true and the total scale ranged from 0 to The subscales also show good content and construct validity .
The derivation of items, and full information on reliability and validity is also available elsewhere . PLIKS-Q quantitative score was computed based on responses to 10 items rated on a 3-point scale yes, definitely; yes, maybe; no, never that assesses positive psychotic experiences hallucinations, delusions and thought interferences.
At least 5 responses were required in order to calculate the total score and the scale ranged from This transformation was selected because it was considered most suitable for previously conducted analyses on these measures and to enable direct comparison between analyses reported elsewhere unpublished and variance explained by the polygenic risk scores PRS.
For comparison polygenic risk analyses were also performed using the van der Waerden transformation and the pattern of results remained unchanged. For the single SNP analyses the psychotic experiences scales as measured by SPEQ and PLIKS-Q were transformed using van der Waerden's transformation  to normalise the data, which works by converting ranked data to the quantiles of the standard normal distribution.
Two-tailed independent t -tests were conducted to describe mean differences between males and females. Where Levene's test was significant, p -values for corrected degrees of freedom df were reported. First, linkage disequilibrium LD clumping at p -value thresholds of 0.
PRS were calculated for eight p -value thresholds p T. Full details of the PCA analyses can be found in .
The initial selection process was informed by the review of the genome-wide association studies GWAS of schizophrenia findings undertaken by Bergen and Petryshen .
Further examination of the original publications was required in order to identify the actual SNPs and corresponding risk alleles from the genes and p -values cited in the review . Three of these variants were significant based on joint analysis of schizophrenia and bipolar disorder. Stringent quality control QC as per the genotyped data was performed.
As a result five of the 33 selected SNPs rs, rs, rs, rs, and rs were excluded from further analyses. The average call rate per individual post exclusion of the five SNPs was Allelic association analyses were performed using an additive linear regression model. Genotypic association analyses were performed using a two degree of freedom joint test of additivity and dominance deviation.
Age and sex were included as covariates in this study. The Bonferroni correction is conservative as it assumes that all tests performed are independent of one another and could therefore result in overcorrection and potential false negatives. For this reason, for significant findings an adaptive permutation approach implemented in PLINK was also employed as it allows the correlational structure between SNPs to be maintained while manipulating the genotype-phenotype relationship to generate appropriate empirical significance levels p EMP.
The composite SNP score was created by summing unweighted risk alleles as per the original publications of the 28 SNPs of the selected 33 that passed QC. Linear regressions were performed to estimate variance explained by the composite SNP score in quantitative psychotic experiences in the validation sample. Two proxies rather than one were selected to ensure that replication was still possible in case of one of the SNPs failing quality control QC.
The average call rate per individual was Age and sex were included as covariates. Paranoia and Hallucinations subscales showed no significant mean differences between sexes although there was a trend for females to report more experiences.
Propensity to psychiatric disease involves the contribution of multiple genetic variants with small individual effects i. This contribution can be summarized using polygenic scores PGSs. The present article discusses the methodological foundations of PGS calculation, together with the limitations and caveats of their use. Furthermore, we show that in terms of using genetic information to address the complexities of mental disorders, PGSs have become a standard tool in psychiatric research. PGS also have the potential for translation into clinical practice.
We performed a genome-wide association study of 3, European individuals with schizophrenia and 3, controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores PRS , as well as specific single nucleotide polymorphisms SNPs previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed.
Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
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We performed a genome-wide association study of 3, European individuals with schizophrenia and 3, controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases. Shaun Purcell Pamela Sklar.
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