A cis-Phase Interaction Study of Genetic Variants Within the MAOA Gene in Major Depressive Disorder

doi:10.1016/j.biopsych.2010.06.004

Biological Psychiatry

Volume 68, Issue 9, 1 November 2010, Pages 795-800

https://doi.org/10.1016/j.biopsych.2010.06.004 Get rights and content

Background

The genetic basis of major depressive disorder (MDD) has been explored extensively, but the mode of transmission of the disease has yet to be established. To better understand the mechanism by which the monoamine oxidase A (MAOA) gene may play a role in developing MDD, the present work examined the cis-phase interaction between genetic variants within the MAOA gene for the pathogenesis of MDD.

Methods

A variable number tandem repeat (VNTR) and 19 single nucleotide polymorphisms (SNPs) within the gene were genotyped in 512 unrelated patients with MDD and 567 unrelated control subjects among a Chinese population. Quantitative real-time polymerase chain reaction analysis was applied to test the effect of genetic variants on expression of the MAOA gene in MDD.

Results

Neither the VNTR polymorphism nor seven informative SNPs showed allelic association with MDD, but the cis-acting interactions between the VNTR polymorphism and four individual SNPs were strongly associated with MDD risk, of which the VNTR-rs1465107 combination showed the strongest association (p = .000011). Quantitative real-time polymerase chain reaction analysis showed that overall relative quantity of MAOA messenger RNA was significantly higher in patients with MDD than in control subjects (fold change = 5.28, p = 1.7 × 10⁻⁷) and that in the male subjects carrying the VNTR-L, rs1465107-A, rs6323-G, rs2072743-A, or rs1137070-T alleles, expression of MAOA messenger RNA was significantly higher in the patient group than in the control group.

Conclusions

The cis-phase interaction between the VNTR polymorphism and functional SNPs may contribute to the etiology of MDD.

Section snippets

Subjects

This study recruited 512 unrelated patients with MDD, of whom 251 were male and 261 were female, aged 28.87 ± 8.32 (SD) years, through the Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China, in the period between January 2006 and August 2008. These patients were diagnosed as having MDD by at least two consultant psychiatrists according to the DSM-IV criteria for MDD (20). Potential participants who were pregnant or had severe medical conditions, abnormal

Results

Of 19 SNPs tested, 12 had a minor allele frequency of <5% and were removed from subsequent analysis. Analysis with the Haploview program showed that the genotypic distributions of all seven highly informative SNPs did not deviate from Hardy-Weinberg equilibrium in female subjects (Table S2 in Supplement 1) and that of these seven SNPs, rs2235186, rs2235185, rs2072744, and rs2072743 were present in the same LD block (D′ > .9 and r2 > .8), while rs1465107, rs6323, and rs1137070 were present

Discussion

Genetic analysis frequently shows that a risk gene may be associated with several complex diseases. Thorgeirsson et al. (26) found that the CHRNA3 gene was associated not only with nicotine dependence but also with lung cancer. Coenen et al. (27) found that the TNFAIP3, IL-2/IL-21, SH2B3, LPP, MMEL1/TNFRSF14, and PFKFB3/PRKCQ genes could confer susceptibility to both rheumatoid arthritis and celiac diseases. Similar findings have also been reported in psychiatric disorders. For example, the

References (40)

Y. Wang et al.
Evidence of epistasis between the catechol-O-methyltransferase and aldehyde dehydrogenase 3B1 genes in paranoid schizophrenia
Biol Psychiatry
(2009)
H.T. Qiu et al.
Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population
Brain Res
(2009)
B. Doornbos et al.
The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT
Prog Neuropsychopharmacol Biol Psychiatry
(2009)
K. Zhang et al.
The combined effects of the 5-HTTLPR and 5-HTR1A genes modulate the relationship between negative life events and major depressive disorder in a Chinese population
J Affect Disord
(2009)
K.J. Livak et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C(T)) Method
Methods
(2001)
K. Ohara et al.
Functional polymorphism of -141C Ins/Del in the dopamine D2 receptor gene promoter and schizophrenia
Psychiatry Res
(1998)
E.S. Lander et al.
Genetic dissection of complex traits
Science
(1994)
R.C. Kessler et al.
The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R)
JAMA
(2003)
K.S. Kendler et al.
A Swedish national twin study of lifetime major depression
Am J Psychiatry
(2006)
B.S. Pickard et al.
Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder
Mol Psychiatry
(2009)

R. Uher

The implications of gene-environment interactions in depression: Will cause inform cure?

Mol Psychiatry

(2008)

C.D. Neff et al.

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

Mol Psychiatry

(2009)

R.H. Belmaker et al.

Major depressive disorder

N Engl J Med

(2008)

J.H. Meyer et al.

Elevated monoamine oxidase A levels in the brain: An explanation for the monoamine imbalance of major depression

Arch Gen Psychiatry

(2006)

T.G. Schulze et al.

Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder

Am J Med Genet

(2000)

S. Jiang et al.

Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes

Am J Med Genet

(2001)

J. Deckert et al.

Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder

Hum Mol Genet

(1999)

A. Caspi et al.

Role of genotype in the cycle of violence in maltreated children

Science

(2002)

D.L. Foley et al.

Childhood adversity, monoamine oxidase A genotype, and risk for conduct disorder

Arch Gen Psychiatry

(2004)

J. Kim-Cohen et al.

MAOA, maltreatment, and gene-environment interaction predicting children's mental health: New evidence and a meta-analysis

Mol Psychiatry

(2006)

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Archival ReportA cis-Phase Interaction Study of Genetic Variants Within the MAOA Gene in Major Depressive Disorder

Background

Methods

Results

Conclusions

Section snippets

Subjects

Results

Discussion

Biol Psychiatry

Brain Res

Prog Neuropsychopharmacol Biol Psychiatry

J Affect Disord

Methods

Psychiatry Res

Genetic dissection of complex traits

Science

The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R)

JAMA

A Swedish national twin study of lifetime major depression

Am J Psychiatry

Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder

Mol Psychiatry

The implications of gene-environment interactions in depression: Will cause inform cure?

Mol Psychiatry

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

Mol Psychiatry

Major depressive disorder

N Engl J Med

Elevated monoamine oxidase A levels in the brain: An explanation for the monoamine imbalance of major depression

Arch Gen Psychiatry

Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder

Am J Med Genet

Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes

Am J Med Genet

Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder

Hum Mol Genet

Role of genotype in the cycle of violence in maltreated children

Science

Childhood adversity, monoamine oxidase A genotype, and risk for conduct disorder

Arch Gen Psychiatry

MAOA, maltreatment, and gene-environment interaction predicting children's mental health: New evidence and a meta-analysis

Mol Psychiatry

Archival Report
A cis-Phase Interaction Study of Genetic Variants Within the MAOA Gene in Major Depressive Disorder