Effect of polymorphisms of three genes mediating monoamine signalling on brain morphometry in schizophrenia and healthy subjects

Abstract

Objective: We examined the effect of risk alleles of polymorphisms of three schizophrenia risk genes that mediate monoamine signalling in the brain on regional brain volumes of schizophrenia and healthy control subjects. The risk alleles and the gene polymorphisms studied were: Val allele of catechol o-methyltransferase (COMT) rs4680 polymorphism; short allele of 5-hydroxy tryptamine transporter linked polymorphic region (5HTTLPR) polymorphism; and T allele of 5-hydroxy tryptamine 2A (5HT2A) rs6314 polymorphism.

Methods: The study was carried out on patients with recent onset schizophrenia (n=41) recruited from the outpatient department of National Institute of Mental Health and Neurosciences, Bangalore, India and healthy control subjects (n=39), belonging to South Indian Dravidian ethnicity. Individual and additive effects of risk alleles of the above gene polymorphisms on brain morphometry were explored using voxel-based morphometry.

Results: Irrespective of phenotypes, individuals with the risk allele T of the rs6314 polymorphism of 5HT2A gene showed greater (at cluster-extent equivalent to family wise error-correction [FWEc] p<0.05) regional brain volumes in the left inferior temporal and left inferior occipital gyri. Those with the risk alleles of the other two polymorphisms showed a trend (at p<0.001, uncorrected) towards lower regional brain volumes. A trend (at p<0.001, uncorrected) towards additive effects of the above 3 risk alleles (subjects with 2 or 3 risk alleles vs. those with 1 or no risk alleles) on brain morphology was also noted.

Conclusions: The findings of the present study have implications in understanding the role of individual and additive effects of genetic variants in mediating regional brain morphometry in health and disease.

Keywords: 5-Hydroxy tryptamine 2A; 5-Hydroxy tryptamine transporter linked polymorphic region; Catechol-O-methyl transferase; Gene polymorphism; Magnetic resonance imaging; Voxel-based morphometry.

Fig. 1

Statistical parametric t-map showing reduced gray matter volumes in schizophrenia subjects (SZ, n=41) in comparison to healthy subjects (HCS, n=39) at (A) family wise error-correction-; height threshold: p<0.001; extent threshold=793 voxels, and (B) uncorrected significance threshold of p<0.001 and an extent threshold of 20 voxels. Total brain volume, age, and gender were entered in the two sample random effects analysis as co-variates. Display according to neurological convention (image left is participant’s left). SPM, statistical parametric mapping.

Fig. 2

Statistical parametric t-map showing increased gray matter volumes in subjects with the risk allele T of rs6314 (5HT2A) polymorphism (n=14) in comparison to those homozygous for the C allele (n=66), irrespective of phenotype, at (A) family wise error-correction threshold (height threshold: p<0.001; extent threshold=988 voxels) and (B) uncorrected significance threshold (p<0.001 and an extent threshold of 20 voxels) irrespective of phenotype. Total brain volume, age, and gender were entered in the two sample random effects analysis as co-variates. Display according to neurological convention (image left is participant’s left). 5HT2A, 5-hydroxy tryptamine 2A; TC, tyrosine-cysteine; CC, cysteine-cysteine; SPM, statistical parametric mapping.

Fig. 3

Statistical parametric t-map showing reduced gray matter volumes associated with the Val allele of COMT rs4680 polymorphism, using dominant model (Val/Val [n=27]+Val/Met [n=34] vs. Met/Met [n=19]), irrespective of phenotype, at uncorrected significance threshold of p<0.001 and an extent threshold of 20 voxels. Total brain volume, age, and gender were entered in the two sample random effects analysis as co-variates. Display according to neurological convention (image left is participant’s left). COMT, catechol o-methyltransferase; Val, valine; Met, methionine; GG, Val/Val; AG, Val/Met; SPM, statistical parametric mapping.

Fig. 4

Statistical parametric t-map map showing reduced gray matter volumes associated with the short allele of 5HTTLPR polymorphism, using the dominant model (short/short [SS, n=25] and long/short [LS, n=38]+long/long [LL, n=17]), irrespective of phenotype, at an uncorrected significance threshold of p<0.001 and an extent threshold of 20 voxels. Total brain volume, age, and gender were entered in the two sample random effects analysis as co-variates. Display according to neurological convention (image left is participant’s left). 5HTTLPR, 5-hydroxy tryptamine transporter linked polymorphic region; SPM, statistical parametric mapping.

Fig. 5

Statistical parametric t-map showing reduced gray matter volumes linked to the additive effect of the three risk alleles S (5HTTLPR), G (rs4680) and T (rs6314) (subjects with 2 or 3 risk alleles [n=53] vs. those with 1 or no risk alleles [n=27]), irrespective of phenotype, at an uncorrected significance threshold of p<0.001 and an extent threshold of 20 voxels. Total brain volume, age, and gender were entered in the two sample random effects analysis as co-variates. Display according to neurological convention (image left is participant’s left). 5HTTLPR, 5-hydroxy tryptamine transporter linked polymorphic region; SPM, statistical parametric mapping.