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

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 147B; no. 5; pp. 543 - 549
• Main Authors: Philibert, Robert A., Sandhu, Harinder, Hollenbeck, Nancy, Gunter, Tracy, Adams, William, Madan, Anup
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 05.07.2008; Wiley-Liss
• Subjects: Addictive behaviors; Adult; Adult and adolescent clinical studies; alcohol dependence; Alcoholism; Alcoholism - genetics; Alcoholism - metabolism; Alcoholism and acute alcohol poisoning; Base Sequence; Biological and medical sciences; Cell Line, Transformed; Depression; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; DNA Methylation; Epigenesis, Genetic - physiology; epigenetics; Female; Genetic Predisposition to Disease; Genotype; Humans; Iowa; major depression; Male; Medical genetics; Medical sciences; methylation; Molecular Sequence Data; Mood disorders; mRNA; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; RNA, Messenger - biosynthesis; serotonin; Serotonin Plasma Membrane Transport Proteins - biosynthesis; Serotonin Plasma Membrane Transport Proteins - genetics; serotonin transporter; Toxicology; Iowa; United States; North America; America; Mood disorder; Human; Typing; Serotonin; Alcoholism; Depression; Genotype; mRNA; Gene expression; Messenger RNA; alcohol dependence; serotonin transporter; Neurotransmitter; Epigenetics; Methylation; major depression
• ISSN: 1552-4841; 1552-485X; 1552-485X
• DOI: 10.1002/ajmg.b.30657

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.