The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies
Open accessAbstract
Serotonin Transporter (5HTT or SLC6A4) mRNA transcription is regulated by both genetic and epigenetic mechanisms. Unfortunately, despite intense scrutiny, the exact identity and contribution of each of these regulatory mechanisms, and their relationship to behavioral illness remain unknown. This lack of knowledge is critical because alterations in SLC6A4 function are posited to be central to a wide variety of CNS disorders. In order to address this shortcoming, we quantified 5HTTLPR genotype, SLC6A4 mRNA production and CpG methylation using biomaterial from 192 lymphoblast cell lines derived from subjects who participated in the latest wave of the Iowa Adoption Studies. We then analyzed the resulting data with respect to clinical characteristics. We confirmed prior findings that the short (s) 5HTTLPR allele is associated with lower amounts of mRNA transcription, but there was no significant effect of the “Long G” allele on mRNA transcription. We also found that CpG methylation was higher (P < 0.0008) and mRNA production (P < 0.0001) was lower in females as compared to males. Those subjects with a lifetime history of Alcohol Dependence had higher levels of SLC6A4 mRNA. There was a trend for an association of increased overall methylation with lifetime history of major depression. Finally, we confirm our prior findings that the exact levels of 5HTT mRNA expression are dependent on how it is measured. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in‐depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness are indicated. © 2007 Wiley‐Liss, Inc.
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Candidate gene studies suggest increased SLC6A4 methylation in depression and bipolar disorder.
“with candidate genes studies suggesting an increased in methylation in depression (Kang et al., 2013; Philibert et al., 2008; Zhao, Goldberg, Bremner, & Vaccarino, 2013), BD (Sugawara et al., 2011)”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Philibert et al., 2008
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- Authors
- Philibert, R. A., Sandhu, H., Hollenbeck, N., Gunter, T., Adams, W., & Madan, A.
- Affiliations
- University of Iowa (US)
- Institute for Systems Biology (US)
- Corresponding author
- Philibert, Robert A.
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2007-11-06
- Volume
- 147B
- Issue
- 5
- Pages
- 543-549
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC3643119
- OpenAlex
- W2022452929
- Cited by
- 300
- References
- 44
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 14 · 2023: 4 · 2022: 10 · 2021: 34 · 2020: 8 · 2019: 8 · 2018: 10 · 2017: 21 · 2016: 22 · 2015: 31 · 2014: 27 · 2013: 19 · 2012: 23
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (R01DA015789, DA015789)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- serotonin transporter, 5-HTTLPR, DNA methylation, CpG methylation, mRNA expression, major depressive disorder, alcoholism, gene expression regulation, epigenetics, genetic polymorphism, sex differences, lymphoblastoid cell lines
- MeSH terms
- Adult, Alcoholism, Base Sequence, Cell Line, Transformed, Depressive Disorder, Major, Major Depressive Disorder, Female, Genotype, Humans, Iowa, Male, Molecular Sequence Data, RNA, Messenger, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic, Serotonin Plasma Membrane Transport Proteins
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