Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease

BACKGROUND: Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. RESULTS: In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD. CONCLUSION: In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD

Genetic Polymorphism in the Serotonin Transporter Promoter Region and Ecological Success in Macaques

A well-characterised sequence length polymorphism in the serotonin transporter promoter region (5-HTTLPR) influences individual behavioural traits and cognitive abilities in humans and rhesus macaques. Macaques have been classified into four continuous grades on the basis of their behavioural attributes, ranging from highly hierarchical and nepotistic species to the most egalitarian and tolerant ones. A comparative study of several species that spanned these grades revealed only rhesus macaques to be polymorphic at the 5-HTTLPR and concluded that the polymorphism was responsible for their despotic and aggressive behaviour (Wendland et al., Behav Genet 36:163–172, 2006). We studied wild populations of three other species and found that the egalitarian and tolerant bonnet and Arunachal macaques are also polymorphic while liontailed macaques, although belonging to the same group, are monomorphic. We thus reject a role for this particular polymorphism in interspecific behavioural variability and show that polymorphic species enjoy greater ecological success possibly due to their higher intraspecific variability in individual behavioural traits

Developing two reference control samples for the Indian population

Human induced Pluripotent Stem Cells (HiPSCs) have immense potential in research and therapeutics. Under the aegis of Department of Biotechnology funded national program entitled, “The Accelerator program for Discovery in Brain Disorders using Stem Cells (ADBS)” we have established a HiPSC biorepository (https://www.ncbs.res.in/adbs/bio-repository) with an objective to study severe mental illness. The repository comprises of HiPSC lines derived from healthy control donors and individuals with life time diagnosis of severe mental illness from dense families. In the current report we submit information regarding two population control reference lines (male = 1; female = 1) from this biorepository

Phylogenetic analysis and selection pressures of 5-HT receptors in human and non-human primates: receptor of an ancient neurotransmitter

Neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) an ancient neurotransmitter, involved in several neurophysiological and behavioral functions, acts by interacting with multiple receptors (5-HT1-5-HT7). Alterations in serotonergic signalling have also been implicated in various psychiatric disorders. The availability of the genome data of nonhuman primates permits comparative analysis of human 5-HT receptors with sequences of non-human primates to understand evolutionary divergence. We compared and analyzed serotonergic receptor sequences from human and non-human primates. Phylogenetic analysis by Maximum Likelihood (ML) method classified human and primate 5-HT receptors into six unique clusters. There was considerable conservation of 5-HT receptor sequences between human and non-human primates; however, a greater diversity at the sub-group level was observed. Compared to the other subgroups, larger multiplicity and expansion was seen within the 5-HT4 receptor subtype in both human and non-human primates. Analysis of non-synonymous and synonymous substitution ratios (Ka/Ks ratio) using the Nei-Gojobori method suggests that 5-HT receptor sequences have undergone negative (purifying) selection over the course of evolution in human, chimpanzee and rhesus monkey. Abnormal human and non-human primate psychopathalogy and behavior, in the context of these variations is discussed. Analysis of these 5-HT receptors in other species will help understand the molecular evolution of 5-HT receptors, and its possible influence on complex behaviors, and psychiatric disorders