Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder: evidence for a role of DRD4

Abstract

The involvement of the mesocorticolimbic dopamine system in behaviors that are compromised in patients with mood disorder has led to the investigation of dopamine system genes as candidates for bipolar disorder. In particular, the functional VNTRs in the exon III of the dopamine D4 (DRD4) and in intron I of the tyrosine hydroxylase (TH) genes have been investigated in numerous association studies that have produced contrasting results. Likewise, linkage studies in multiplex bipolar families have shown both positive and negative results for markers in close proximity to DRD4 and TH on 11p15.5. We performed a linkage disequilibrium analysis of the DRD4 and TH VNTRs in a sample of 145 nuclear families comprised of DSM-IV bipolar probands and their biological parents. An excess of transmissions and non transmissions was observed for the DRD4 4-and 2-repeat alleles respectively. The biased transmission showed a parent of origin effect (POE) since it was derived almost exclusively from the maternal meiosis (4-repeat allele maternally transmitted 40 times vs 20 times non-transmitted; 2 = 6.667; df = 1; P = 0.009; while paternally transmitted 26 times vs 21 times nontransmitted; 2 = 0.531; df = 1; P = 0.46). The analysis of TH did not reveal biased transmission of intron I VNTR alleles. Although replication of our study is necessary, the fact that DRD4 exhibit POE and is located on 11p15.5, in close proximity to a cluster of imprinted genes, suggests that genomic imprinting may be operating in bipolar disorder.

Epigenetics in mood disorders

“…Such studies have detected several additional linkage loci suggestive of imprinting: 13q12, 1q41 [46], 2p24-21, 2q31-q32, 14q32, and 16q21-q23 [48]. Transmission disequilibrium tests in trio samples also revealed the association of several genes when the gender of the transmitting parent was taken into consideration [49,50]. None of these linkages or findings in association studies suggestive of imprinting have as yet been validated by molecular biological experiments to show allele-specific expression or methylation.…”

Bipolar Disorder: Diagnosis, Neuroanatomical and Biochemical Background

“…Studies involving adoption, twins and family reveal a genetic predisposition to developing bipolar disorder (Gershon et al, 1990;Muglia et al, 2002). A multitude of genes interacting with each other as well as with the environment is most likely lead to a multifactorial mode of inheritance for bipolar disorder (Berrettini W.H, 1999;Muglia et al, 2002).…”

“…Studies involving adoption, twins and family reveal a genetic predisposition to developing bipolar disorder (Gershon et al, 1990;Muglia et al, 2002). A multitude of genes interacting with each other as well as with the environment is most likely lead to a multifactorial mode of inheritance for bipolar disorder (Berrettini W.H, 1999;Muglia et al, 2002). A significant association was reported between two single nucleotide polymorphisms (rs4952 and rs4953) in the human beta 3 nicotinic acetylcholoine receptor subunit gene (CHRNB3) on chromosome 8 and bipolar disorder (Hartz et al, 2011).…”

“…This particular region incorporates the tyrosine hydroxylase (TH) and the dopamine D4 receptor gene (DRD4) (Todd et al, 1996;Oruc et al, 1997;Furlong et al, 1999;Li et al, 1999;Serretti et al, 2001). Tyrosine hydroxylase plays a significant role in the formation of dopamine since it is the key and rate-limiting enzyme of the catecholamine synthesis converting tyrosine to DOPA, a precursor of dopamine (Muglia et al, 2002). DRD4 has been noted to be highly polymorphic, consisting of 2-10 tandem repeats in the third exon, encoding the receptor's longest loop (Asghari et al, 1995;Muglia et al, 2002).…”

“…Tyrosine hydroxylase plays a significant role in the formation of dopamine since it is the key and rate-limiting enzyme of the catecholamine synthesis converting tyrosine to DOPA, a precursor of dopamine (Muglia et al, 2002). DRD4 has been noted to be highly polymorphic, consisting of 2-10 tandem repeats in the third exon, encoding the receptor's longest loop (Asghari et al, 1995;Muglia et al, 2002). The gene for tyrosine hydroxylase contains a microsatellite known as HUMTH01, which has been proposed to play a regulatory role in its expression (Meloni et al, 1998).…”