Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (>10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations.

Summary Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction, we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations and that these mechanisms most likely have markedly different rates and selective pressures than those leading to point mutations.

BackgroundAlzheimer’s disease (AD) is one of the leading genetically complex and heterogeneous disorder that is influenced by both genetic and environmental factors. The underlying risk factors remain largely unclear for this heterogeneous disorder. In recent years, high throughput methodologies, such as genome-wide linkage analysis (GWL), genome-wide association (GWA) studies, and genome-wide expression profiling (GWE), have led to the identification of several candidate genes associated with AD. However, due to lack of consistency within their findings, an integrative approach is warranted. Here, we have designed a rank based gene prioritization approach involving convergent analysis of multi-dimensional data and protein-protein interaction (PPI) network modelling.ResultsOur approach employs integration of three different AD datasets- GWL,GWA and GWE to identify overlapping candidate genes ranked using a novel cumulative rank score (SR) based method followed by prioritization using clusters derived from PPI network. SR for each gene is calculated by addition of rank assigned to individual gene based on either p value or score in three datasets. This analysis yielded 108 plausible AD genes. Network modelling by creating PPI using proteins encoded by these genes and their direct interactors resulted in a layered network of 640 proteins. Clustering of these proteins further helped us in identifying 6 significant clusters with 7 proteins (EGFR, ACTB, CDC2, IRAK1, APOE, ABCA1 and AMPH) forming the central hub nodes. Functional annotation of 108 genes revealed their role in several biological activities such as neurogenesis, regulation of MAP kinase activity, response to calcium ion, endocytosis paralleling the AD specific attributes. Finally, 3 potential biochemical biomarkers were found from the overlap of 108 AD proteins with proteins from CSF and plasma proteome. EGFR and ACTB were found to be the two most significant AD risk genes.ConclusionsWith the assumption that common genetic signals obtained from different methodological platforms might serve as robust AD risk markers than candidates identified using single dimension approach, here we demonstrated an integrated genomic convergence approach for disease candidate gene prioritization from heterogeneous data sources linked to AD.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-199) contains supplementary material, which is available to authorized users.

The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.

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Colchicine is a medication most commonly used in the treatment of gout and familial mediterannean fever. A rare complication of therapy is toxicity causing proximal myopathy and polyneuropathy. Colchicine myopathy has been associated with the coadministration of other medications with colchicine, such as statins or tacrolimus, and is more common in patients with renal impairment. Otherwise, it is unclear which patients are at greatest risk of developing this adverse drug reaction. ABCB1 is important to the metabolism of colchicine, so we speculated that it was possible that colchicine myopathy patients may have a particular genotype that is associated with this side effect. We describe two cases of colchicine myopathy which occurred with co-administration of rosuvastatin. From one case, we present the first published data on muscle MRI in this condition. We additionally present an analysis of four genetic polymorphisms in ABCB1 and transcript levels in muscle tissue, and demonstrate the descriptive finding of reduced ABCB1 transcript levels in the colchicine myopathy patients.

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Spastic cerebral palsy (CP) is the one of most common neurological disorders occurring due to damage to the immature brain or any other brain lesion at the time of birth. To aid in making the life of the CP patient meaningful, several interventions such as medical, surgical and rehabilitation have been employed to date. Besides these, recently repetitive Transcranial magnetic stimulation (r-TMS) is a new found approach which is being employed for treating various neurological and psychological conditions. The aim of this study was to observe the effects of r-TMS on muscle spasticity in CP patients by stimulating the motor cortex area of the brain, which is responsible for muscle movements. In this study, 20 subjects diagnosed with CP were recruited and 10 each were placed in two groups, namely the research group (RG) (mean age, height and weight were 7.99 (SD = 4.66) years, 116.7 (SD = 23.57) cm and 21.40 (SD = 10.95) kg, respectively) and the control group (CG) (mean age, height and weight were 8.41 (SD = 4.32) years, 107.9 (SD = 26.33) cm, 21.40 (SD = 12.63) kg, respectively). r-TMS frequencies of 5 Hz and 10 Hz were administered for 15 min daily to patients in RG followed by standard therapy (ST) of 1 h duration daily for 20 days. Moreover, the patients in the control group (CG) were given only standard therapy (ST) of 1 h duration for 20 days. Modified Ashworth Scale (MAS) was used as an outcome measure to determine the level of muscle spasticity. A pre- assessment of MAS score was performed on both RG and CG to determine the level of spasticity prior to starting therapy; and similarly post-assessment after 20 days was done to observe the changes post-therapy. Statistical analysis of pre vs post MAS scores showed that few muscles showed reduction in muscle tightness after administering only ST in the CG. On the contrary, the RG that underwent r-TMS therapy combined with ST showed a significant decrease (p < 0.05) in muscle tightness for all the muscles selected for the therapy.