Evaluating historical candidate genes for schizophrenia
Open accessAbstract
Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.
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The reproducible yield of candidate gene association studies is negligible compared with current knowledge.
“Compared to current knowledge, the reproducible yield of candidate gene association studies is negligible (Farrell et al., 2015).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Farrell et al., 2015
Linkage and candidate gene studies produced many claims of gene discovery for SCZ, such as COMT, DISC1, DTNBP1, and NRG1, that were not subsequently supported.
“Linkage and candidate gene studies led to many claims of gene discovery (e.g., COMT, DISC1, DTNBP1, and NRG1 for SCZ) that were not subsequently supported (Border et al., In press; Farrell et al., 2015).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Farrell et al., 2015
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Genetic and functional analysis reveals TENM4 contributes to schizophrenia
Yi, X., Li, M., He, G., Du, H., Li, X.-W., Cao, D., Wang, L., Wu, X., Yang, F.-P., Chen, X., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103063 · Cited by 21 · see citing works
DISC1 is a coordinator of intracellular trafficking to shape neuronal development and connectivity
Devine, M. J., Norkett, R., & Kittler, J. T. (2016) · The Journal of Physiology · doi:10.1113/jp272187 · Cited by 27 · see citing works
Tomoda, T., Hikida, T., & Sakurai, T. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0556-5 · Cited by 27 · see citing works
Can delusions play a protective role?
Gunn, R., & Bortolotti, L. (2018) · Phenomenology and the Cognitive Sciences · doi:10.1007/s11097-017-9555-6 · Cited by 27 · see citing works
Ying, J., Chew, Q. H., McIntyre, R. S., & Sim, K. (2023) · Genes · doi:10.3390/genes14030689 · Cited by 26 · see citing works
How Good Were Candidate Gene Guesses in Schizophrenia Genetics?
Sullivan, P. F. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.09.004 · Cited by 25 · see citing works
Self-citation
- Authors
- Farrell, M. S., Werge, T., Sklar, P., Owen, M. J., Ophoff, R. A., O'Donovan, M. C., Corvin, A., Cichon, S., & Sullivan, P. F.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Copenhagen (DK)
- Icahn School of Medicine at Mount Sinai (US)
- Cardiff University (GB)
- University of California, Los Angeles (US)
- Trinity College Dublin (IE)
- University of Bonn (DE)
- Corresponding author
- Sullivan, P F
- Venue
- Molecular Psychiatry
- Published
- 2015-03-10
- Volume
- 20
- Issue
- 5
- Pages
- 555-562
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4414705
- OpenAlex
- W1987942611
- Cited by
- 315
- References
- 95
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 17 · 2023: 17 · 2022: 21 · 2021: 33 · 2020: 49 · 2019: 35 · 2018: 33 · 2017: 43 · 2016: 44 · 2015: 5
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- UNC Libraries
- Funders
- Lundbeckfonden (R155-2014-1724)
- Medical Research Council (MR/L010305/1)
- National Institute of Mental Health (R01MH077139, U01MH085520, MH085520, MH077139)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, candidate genes, catechol-O-methyltransferase, DISC1, DTNBP1, neuregulin-1, common genetic variants, statistical power, genetic basis of schizophrenia
- MeSH terms
- Genotype, Humans, Schizophrenia, Genetic Variation, Genetic Predisposition to Disease, Genomics, PubMed, History, 20th Century, History, 21st Century, Genome-Wide Association Study
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