Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism

Scott Davidson, Marissa Lear, Lynne Shanley, Benjamin Hing, Amanda Baizan-Edge, Annika Herwig, John P Quinn, Gerome Breen, Peter McGuffin, Andrew Starkey, Perry Barrett, Alasdair Mackenzie

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The expression of the galanin gene (GAL) in the paraventricular nucleus (PVN) and in the amygdala of higher vertebrates suggests the requirement for highly conserved, but unidentified, regulatory sequences that are critical to allow the galanin gene to control alcohol and fat intake and modulate mood. We used comparative genomics to identify a highly conserved sequence that lay 42¿kb 5' of the human GAL transcriptional start site that we called GAL5.1. GAL5.1 activated promoter activity in neurones of the PVN, arcuate nucleus and amygdala that also expressed the galanin peptide. Analysis in neuroblastoma cells demonstrated that GAL5.1 acted as an enhancer of promoter activity after PKC activation. GAL5.1 contained two polymorphisms; rs2513280(C/G) and rs2513281(A/G), that occurred in two allelic combinations (GG or CA) where the dominant GG alelle occurred in 70-83¿% of the human population. Intriguingly, both SNPs were found to be in LD (R(2) of 0.687) with another SNP (rs2156464) previously associated with major depressive disorder (MDD). Recreation of these alleles in reporter constructs and subsequent magnetofection into primary rat hypothalamic neurones showed that the CA allele was 40¿% less active than the GG allele. This is consistent with the hypothesis that the weaker allele may affect food and alcohol preference. The linkage of the SNPs analysed in this study with a SNP previously associated with MDD together with the functioning of GAL5.1 as a PVN and amygdala specific enhancer represent a significant advance in our ability to understand alcoholism, obesity and major depressive disorder.
Original languageEnglish
Pages (from-to)2211-2221
Number of pages11
JournalNeuropsychopharmacology
Volume36
Issue number11
DOIs
Publication statusPublished - Oct 2011

Fingerprint

Galanin
Amygdala
Alcoholism
Hypothalamus
Single Nucleotide Polymorphism
Paraventricular Hypothalamic Nucleus
Major Depressive Disorder
Obesity
Alleles
Depression
Alcohols
Neurons
Food Preferences
Recreation
Arcuate Nucleus of Hypothalamus
Aptitude
Conserved Sequence
Genomics
Neuroblastoma
Genes

Cite this

Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala : implications for obesity, depression and alcoholism. / Davidson, Scott; Lear, Marissa; Shanley, Lynne; Hing, Benjamin; Baizan-Edge, Amanda; Herwig, Annika; Quinn, John P; Breen, Gerome; McGuffin, Peter; Starkey, Andrew; Barrett, Perry; Mackenzie, Alasdair.

In: Neuropsychopharmacology, Vol. 36, No. 11, 10.2011, p. 2211-2221.

Research output: Contribution to journalArticle

Davidson, Scott ; Lear, Marissa ; Shanley, Lynne ; Hing, Benjamin ; Baizan-Edge, Amanda ; Herwig, Annika ; Quinn, John P ; Breen, Gerome ; McGuffin, Peter ; Starkey, Andrew ; Barrett, Perry ; Mackenzie, Alasdair. / Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala : implications for obesity, depression and alcoholism. In: Neuropsychopharmacology. 2011 ; Vol. 36, No. 11. pp. 2211-2221.
@article{a934a4788b1e4062b2a34cd6781201ad,
title = "Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism",
abstract = "The expression of the galanin gene (GAL) in the paraventricular nucleus (PVN) and in the amygdala of higher vertebrates suggests the requirement for highly conserved, but unidentified, regulatory sequences that are critical to allow the galanin gene to control alcohol and fat intake and modulate mood. We used comparative genomics to identify a highly conserved sequence that lay 42¿kb 5' of the human GAL transcriptional start site that we called GAL5.1. GAL5.1 activated promoter activity in neurones of the PVN, arcuate nucleus and amygdala that also expressed the galanin peptide. Analysis in neuroblastoma cells demonstrated that GAL5.1 acted as an enhancer of promoter activity after PKC activation. GAL5.1 contained two polymorphisms; rs2513280(C/G) and rs2513281(A/G), that occurred in two allelic combinations (GG or CA) where the dominant GG alelle occurred in 70-83¿{\%} of the human population. Intriguingly, both SNPs were found to be in LD (R(2) of 0.687) with another SNP (rs2156464) previously associated with major depressive disorder (MDD). Recreation of these alleles in reporter constructs and subsequent magnetofection into primary rat hypothalamic neurones showed that the CA allele was 40¿{\%} less active than the GG allele. This is consistent with the hypothesis that the weaker allele may affect food and alcohol preference. The linkage of the SNPs analysed in this study with a SNP previously associated with MDD together with the functioning of GAL5.1 as a PVN and amygdala specific enhancer represent a significant advance in our ability to understand alcoholism, obesity and major depressive disorder.",
author = "Scott Davidson and Marissa Lear and Lynne Shanley and Benjamin Hing and Amanda Baizan-Edge and Annika Herwig and Quinn, {John P} and Gerome Breen and Peter McGuffin and Andrew Starkey and Perry Barrett and Alasdair Mackenzie",
year = "2011",
month = "10",
doi = "10.1038/npp.2011.93",
language = "English",
volume = "36",
pages = "2211--2221",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala

T2 - implications for obesity, depression and alcoholism

AU - Davidson, Scott

AU - Lear, Marissa

AU - Shanley, Lynne

AU - Hing, Benjamin

AU - Baizan-Edge, Amanda

AU - Herwig, Annika

AU - Quinn, John P

AU - Breen, Gerome

AU - McGuffin, Peter

AU - Starkey, Andrew

AU - Barrett, Perry

AU - Mackenzie, Alasdair

PY - 2011/10

Y1 - 2011/10

N2 - The expression of the galanin gene (GAL) in the paraventricular nucleus (PVN) and in the amygdala of higher vertebrates suggests the requirement for highly conserved, but unidentified, regulatory sequences that are critical to allow the galanin gene to control alcohol and fat intake and modulate mood. We used comparative genomics to identify a highly conserved sequence that lay 42¿kb 5' of the human GAL transcriptional start site that we called GAL5.1. GAL5.1 activated promoter activity in neurones of the PVN, arcuate nucleus and amygdala that also expressed the galanin peptide. Analysis in neuroblastoma cells demonstrated that GAL5.1 acted as an enhancer of promoter activity after PKC activation. GAL5.1 contained two polymorphisms; rs2513280(C/G) and rs2513281(A/G), that occurred in two allelic combinations (GG or CA) where the dominant GG alelle occurred in 70-83¿% of the human population. Intriguingly, both SNPs were found to be in LD (R(2) of 0.687) with another SNP (rs2156464) previously associated with major depressive disorder (MDD). Recreation of these alleles in reporter constructs and subsequent magnetofection into primary rat hypothalamic neurones showed that the CA allele was 40¿% less active than the GG allele. This is consistent with the hypothesis that the weaker allele may affect food and alcohol preference. The linkage of the SNPs analysed in this study with a SNP previously associated with MDD together with the functioning of GAL5.1 as a PVN and amygdala specific enhancer represent a significant advance in our ability to understand alcoholism, obesity and major depressive disorder.

AB - The expression of the galanin gene (GAL) in the paraventricular nucleus (PVN) and in the amygdala of higher vertebrates suggests the requirement for highly conserved, but unidentified, regulatory sequences that are critical to allow the galanin gene to control alcohol and fat intake and modulate mood. We used comparative genomics to identify a highly conserved sequence that lay 42¿kb 5' of the human GAL transcriptional start site that we called GAL5.1. GAL5.1 activated promoter activity in neurones of the PVN, arcuate nucleus and amygdala that also expressed the galanin peptide. Analysis in neuroblastoma cells demonstrated that GAL5.1 acted as an enhancer of promoter activity after PKC activation. GAL5.1 contained two polymorphisms; rs2513280(C/G) and rs2513281(A/G), that occurred in two allelic combinations (GG or CA) where the dominant GG alelle occurred in 70-83¿% of the human population. Intriguingly, both SNPs were found to be in LD (R(2) of 0.687) with another SNP (rs2156464) previously associated with major depressive disorder (MDD). Recreation of these alleles in reporter constructs and subsequent magnetofection into primary rat hypothalamic neurones showed that the CA allele was 40¿% less active than the GG allele. This is consistent with the hypothesis that the weaker allele may affect food and alcohol preference. The linkage of the SNPs analysed in this study with a SNP previously associated with MDD together with the functioning of GAL5.1 as a PVN and amygdala specific enhancer represent a significant advance in our ability to understand alcoholism, obesity and major depressive disorder.

U2 - 10.1038/npp.2011.93

DO - 10.1038/npp.2011.93

M3 - Article

VL - 36

SP - 2211

EP - 2221

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 11

ER -