Molecular genetics of neuropsychiatric illness: some musings.

Research into the genetic underpinnings of neuropsychiatric illness has occurred at many levels. As more information accumulates, it appears that many approaches may each offer their unique perspective. The search for low penetrance and common variants, that may mediate risk, has necessitated the formation of many international consortia, to pool resources, and achieve the large sample sizes needed to discover these variants. There has been the parallel development of statistical methods to analyse large datasets and present summary statistics which allows data comparison across studies. Even so, the results of studies on well-characterised clinical datasets of modest sizes can be enlightening and provide important clues to understanding these complex disorders. We describe the use of common variants, at multiallelic loci like TOMM40 and APOE to study dementia, weighted genetic risk scores for alcohol-induced liver cirrhosis and whole exome sequencing to identify rare variants in genes like PLA2G6 in familial psychoses and schizophrenia in our Indian population.

Association study of BDNF Val66Met gene polymorphism with bipolar disorder and lithium treatment response in Indian population.

BACKGROUND: The association of the Val66Met (rs6265) polymorphism in the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its association with lithium treatment response. METHODS: BD patients (N = 301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ⩾7 were defined as lithium responders (N = 115) and patients with score <7 were defined as lithium non-responders (N = 75). Healthy controls (N = 484) with no lifetime history of neuropsychiatric illness or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay. RESULTS: Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p = 0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p = 0.008) in BD patients. However, no significant difference is noted in genotype or allele frequencies of this polymorphism between the lithium responders and non-responders. CONCLUSIONS: The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but it is not related to response to lithium.

Higher interleukin-33 levels in aggressive periodontitis cases.

CONTEXT: Interleukin-33 (IL-33) is a novel alarmin that warns immune cells of tissue destruction in injury or infection. AIMS: This study is aimed at analyzing and correlating the concentration of IL-33 in the gingival crevicular fluid (GCF) and plasma of healthy subjects and chronic and aggressive periodontitis patients with intronic variant single nucleotide polymorphisms (SNPs), rs1157505 (C/G) and rs7044343 (C/T) in the IL-33 gene. SETTINGS AND DESIGN: This is a cross-sectional, biochemical, genetic study. MATERIALS AND METHODS: Ninety subjects were divided into Group H: subjects with healthy periodontium, Group CP: chronic periodontitis patients, and Group GAgP: generalized aggressive periodontitis patients, based on clinical parameters of periodontal inflammation. IL-33 concentration in GCF, as well as plasma, was quantified using enzyme-linked immunosorbent assay. The SNPs rs1157505 and rs7044343 were analyzed using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: A significant difference was found in IL-33 concentration in GCF and plasma between the three groups. GG genotype of IL-33 SNP rs1157505 was associated with the highest GCF and plasma IL-33 concentration and was significantly more in GAgP than healthy or CP groups. IL-33 SNP rs7044343 did not show any such association. All GAgP patients had the highest GCF and plasma concentration of IL-33. CONCLUSIONS: IL-33 may be a potential inflammatory marker of periodontitis. GG genotype of SNP rs1157505 may be associated with GAgP.

Does retinoic acid reverse cell cycle dysregulation in Alzheimer's disease lymphocytes?

Aberrant re-entry of neurons into cell cycle appears to be an early event in Alzheimer's disease (AD) and targeting this dysregulation may have therapeutic potential. We have examined whether cell cycle dysregulation in AD can be detected using patient and control derived B-lymphocytes. Cell cycle analysis using flow cytometry demonstrated that cell cycle dysregulation occurs in AD lymphocytes, with a significant difference in the distribution of cells in G0/G1, S and G2/M phases of cell cycle as compared to control lymphocytes. Using global gene expression analysis by RNA sequencing and cell cycle analysis, we examined the role of Retinoic Acid (RA), a candidate molecule predicted to be of therapeutic potential in cell cycle dysregulation associated with AD. CCND1, CCNE2, E2F transcription factors which are known to be dysregulated in AD were among the 32 genes that showed differential expression in response to RA treatment thus suggesting a protective role of RA. However, the cell cycle analysis demonstrated that RA did not reverse the cellular phenotype in AD lymphocytes. This suggests that though RA might have a protective role by influencing the expression of cell cycle genes, it might not be able to arrest abnormal re-entry into cell cycle.

Mutation burden profile in familial Alzheimer's disease cases from India.

This study attempts to identify coding risk variants in genes previously implicated in Alzheimer's disease (AD) pathways, through whole-exome sequencing of subjects (N = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg > tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D). The mutation burden assessment of dementia-related genes for all 17 cases revealed 45 variants, which were either shared across subjects, or were present in just the 1 patient. The study shows that the clinical characteristics, and genetic correlates, obtained in this sample are broadly comparable to the other studies that have investigated familial forms of AD. Our study identifies rare deleterious genetic variations, in the coding region of genes involved in amyloid signaling, and other dementia-associated pathways.

BDNF gene and obsessive compulsive disorder risk, symptom dimensions and treatment response.

AIM: Genetic etiology of Obsessive Compulsive Disorder (OCD) has been investigated extensively, with mixed results across candidate gene studies. The dimensional subtypes of OCD are shown to better correlate with brain imaging endophenotypes and thus could potentially enhance the power of genetic association. In this study, we perform a case control analysis of association of a single nucleotide polymorphism rs6265(Val66Met) in Brain Derived Neurotrophic Factor gene, that has been previously implicated in a variety of psychiatric syndromes, and examine its association with symptom dimensions of OCD. METHODS: Individuals diagnosed to have OCD (n=377) and controls (n=449) of South Indian origin were genotyped for polymorphism rs6265 (196G/A, Val66Met). Detailed phenotypic assessment of the cases were carried out in the cases using structured instruments. The genotypic association was tested for clinical variables such as age of onset, gender, family history, co-morbidity, treatment response, and factor analyzed OCD symptom dimensions. RESULTS: The allele 'A' frequency was found to be significantly higher in the controls, as compared to cases suggesting a protective effect. The contamination/washing symptom dimension score was significantly lower in carriers of 'A' allele which remained significant even after testing for confounding effects on linear regression. CONCLUSIONS: Our results support findings from previous studies on a possible protective effect of the 'Met' allele at the Val66Met locus in OCD. Its association with lower scores on the contamination/washing dimension is a novel finding of this study.

An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India.

Multiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N=38) and healthy subjects (N=37) from South India. Patients with schizophrenia showed trend-level (p<0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia.