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      Seminal Contributions of Timothy J. Crow

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          Abstract

          We recall the life and work of Timothy J. Crow, whose contributions provided great insights into the pathophysiology of schizophrenia and continue to shape many questions in the field. We compile his key works relating to psychotic disorders, focusing on the trajectory of his theoretical stance. Our account is interlaced with our own interpretation of the evidence that influenced Crow’s arguments over the years as well as his scientific method. Crow has had a significant impact on the neuroscience of schizophrenia. Many of his observations are still valid and several questions he raised remain unanswered to date.

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          Mapping genomic loci implicates genes and synaptic biology in schizophrenia

          Vassily V. Trubetskoy, Antonio F. Pardiñas, Ting Qi … (2022)
          Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
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            Schizophrenia: a concise overview of incidence, prevalence, and mortality.

            J. McGrath, S. Saha, D. CHANT … (2008)
            Recent systematic reviews have encouraged the psychiatric research community to reevaluate the contours of schizophrenia epidemiology. This paper provides a concise overview of three related systematic reviews on the incidence, prevalence, and mortality associated with schizophrenia. The reviews shared key methodological features regarding search strategies, analysis of the distribution of the frequency estimates, and exploration of the influence of key variables (sex, migrant status, urbanicity, secular trend, economic status, and latitude). Contrary to previous interpretations, the incidence of schizophrenia shows prominent variation between sites. The median incidence of schizophrenia was 15.2/100,000 persons, and the central 80% of estimates varied over a fivefold range (7.7-43.0/100,000). The rate ratio for males:females was 1.4:1. Prevalence estimates also show prominent variation. The median lifetime morbid risk for schizophrenia was 7.2/1,000 persons. On the basis of the standardized mortality ratio, people with schizophrenia have a two- to threefold increased risk of dying (median standardized mortality ratio = 2.6 for all-cause mortality), and this differential gap in mortality has increased over recent decades. Compared with native-born individuals, migrants have an increased incidence and prevalence of schizophrenia. Exposures related to urbanicity, economic status, and latitude are also associated with various frequency measures. In conclusion, the epidemiology of schizophrenia is characterized by prominent variability and gradients that can help guide future research.
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              Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

              Thalia Eley, Caroline Hayward, Nicholas G Martin … (2018)
              Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 1254142
                Journal ID (nlm-ta): Psychol Med
                Journal ID (iso-abbrev): Psychol Med
                Title: Psychological medicine
                ISSN (Print): 0033-2917
                ISSN (Electronic): 1469-8978
                Publication date Nihms-submitted: 25 January 2025
                Publication date (Electronic): 7 March 2025
                Publication date PMC-release: 19 March 2025
                Volume: 55
                Electronic Location Identifier: e75
                Affiliations
                [1 ]Douglas Mental Health University Institute ( https://ror.org/05dk2r620) , Department of Psychiatry, McGill University ( https://ror.org/01pxwe438) , QC, Canada
                [2 ]Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario ( https://ror.org/02grkyz14) London, ON, Canada
                [3 ]Robarts Research Institute ( https://ror.org/01psf3m26) & Lawson Health Research Institute, London, ON, Canada
                [4 ]Institute of Mental Health ( https://ror.org/015dvxx67) , University of Nottingham ( https://ror.org/01ee9ar58) , Nottingham, UK
                Author notes
                Address correspondence to: Dr. Lena Palaniyappan, Room T-101, Douglas Hospital, 6875, Boulevard Lasalle, Verdun, Canada. lena.palaniyappan@ 123456mcgill.ca
                Article
                Manuscript ID: EMS202863
                DOI: 10.1017/S0033291725000182
                PMC ID: 7617505
                PubMed ID: 40109883
                SO-VID: 6c86484f-e894-423e-a0cb-b0e5822246ea
                License:

                This work is licensed under a BY 4.0 International license.

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                ScienceOpen disciplines: Clinical Psychology & Psychiatry
                Keywords: psychosis,continuum,evolution,pathophysiology,subtypes,asymmetry,language,sex
                Data availability:
                ScienceOpen disciplines: Clinical Psychology & Psychiatry
                Keywords: psychosis, continuum, evolution, pathophysiology, subtypes, asymmetry, language, sex

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