| 1. |
- Purcell, Shaun M., et al.
(author)
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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
- 2009
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 460:7256, s. 748-752
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Journal article (peer-reviewed)abstract
- Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 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.
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| 2. |
- Hannon, Eilis, et al.
(author)
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DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
- 2021
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In: eLIFE. - : eLife Sciences Publications. - 2050-084X. ; 10
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Journal article (peer-reviewed)abstract
- We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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| 3. |
- Ormond, Cathal, et al.
(author)
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Whole genome sequencing study of identical twins discordant for psychosis
- 2024
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In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 14:1
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Journal article (peer-reviewed)abstract
- Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.
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