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A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

ABSTRACT: This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N?=?515), lateral ventricular volume (N?=?798), and the cognitive measures block design (N?=?3,089), digit span (N?=?1,437), and the Ray Auditory Verbal Learning Task (N?=?2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p?=?0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p?=?0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p?=?0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

SUBMITTER: Ranlund S

PROVIDER: S-EPMC5763362 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

Ranlund Siri S Calafato Stella S Thygesen Johan H JH Lin Kuang K Cahn Wiepke W Crespo-Facorro Benedicto B de Zwarte Sonja M C SMC Díez Álvaro Á Di Forti Marta M Iyegbe Conrad C Jablensky Assen A Jones Rebecca R Hall Mei-Hua MH Kahn Rene R Kalaydjieva Luba L Kravariti Eugenia E McDonald Colm C McIntosh Andrew M AM McQuillin Andrew A Picchioni Marco M Prata Diana P DP Rujescu Dan D Schulze Katja K Shaikh Madiha M Toulopoulou Timothea T van Haren Neeltje N van Os Jim J Vassos Evangelos E Walshe Muriel M Lewis Cathryn C Murray Robin M RM Powell John J Bramon Elvira E

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20170829 1

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the ...[more]

PMID: 28851104

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Project description:BackgroundThe genetic architecture of psychotic disorders is complex, with hundreds of genetic risk loci contributing to a polygenic model of disease. Overlap in the genetics of psychotic disorders and brain measures has been found in European populations, but has not been explored in populations of African ancestry. The aim of this study was to determine whether a relationship exists between a schizophrenia-derived PRS and (i) methamphetamine associated psychosis (MAP), and (ii) brain structural measures, in a South African population.MethodsThe study sample consisted of three participant groups: 31 individuals with MAP, 48 with apsychotic methamphetamine dependence, and 49 healthy controls. Using PRSice, PRS was generated for each of the participants with GWAS summary statistics from the Psychiatric Genomics Consortium Schizophrenia working group (PGC-SCZ2) as the discovery dataset. Regression analyses were performed to determine associations of PRS, with diagnosis, whole brain, and regional gray and white matter measures.ResultsSchizophrenia-derived PRS did not significantly predict MAP diagnosis. After correction for multiple testing, no significant associations were found between PRS and brain measures across all groups.DiscussionThe lack of significant associations here may indicate that the study is underpowered, that brain volumes in MAP are due to factors other than polygenic risk for schizophrenia, or that PRS derived from a largely European discovery set has limited utility in individuals of African ancestry. Larger studies, that include diverse populations, and more nuanced brain measures, may help elucidate the relationship between schizophrenia-PRS, brain structural changes, and psychosis.ConclusionThis research presents the first PRS study to investigate shared genetic effects across psychotic disorders and brain structural measures in an African population. Ancestrally comparable discovery datasets may be useful for future African genetic research.

Project description:OBJECTIVE:The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. METHODS:Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. RESULTS:For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. CONCLUSIONS:The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

Dataset Information

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

Publications

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

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