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Neurofibromatosis type 1 (NF1) is a multisystemic hereditary disorder associated with an increased risk of benign and malignant tumor formation predominantly on the skin, bone, and peripheral nervous system. It has been reported that out of all the NF1 cases, more than 95% cases develop the disease due to heterozygous loss-of-function variants in Neurofibromin (NF1) gene. However, identification of NF1 causative variants by presently recommended method of gene-targeted Sanger sequencing is challenging and cost-intensive due to the large size of the NF1gene with 60 exons spanning about 350 kb. Further, conducting the genetic studies is difficult in low resource regions and among families with the limited financial capabilities, restricting them from availing diagnostic as well as proper disease management measures. Here, we studied a three-generation family from Jammu and Kashmir state in India, with multiple affected family members showing clinical indications of NF1. We combinedly used two applications, Whole Exome Sequencing (WES) and Sanger sequencing, for this study and discovered a nonsense variant NM_000267.3:c.2041C>T (NP_000258.1:p.Arg681Ter*) in exon 18 of NF1 gene in a cost effective manner. In silico analyses further substantiated the pathogenicity of this novel variant. The study also emphasized on the role of Next Generation Sequencing (NGS) as a cost-effective method for the discovery of pathogenic variants in disorders with known phenotypes found in large sized candidate genes. The current study is the first study based on the genetic characterization of NF1 from Jammu and Kashmir–India, highlighting the importance of the described methodology adopted for the identification and understanding of the disease in low resource region. The early diagnosis of genetic disorders would open the door to appropriate genetic counseling, reducing the disease burden in the affected families and the general population at large. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is a cluster of heritable and related traits which has been associated with a range of pathophysiological factors including dyslipidaemia, abdominal obesity, increased fasting plasma glucose (FPG) and hypertension. The documented genetic basis of the metabolic syndrome include several chromosomal positions, numerous candidate gene-associated polymorphisms, different genetic variants, which are linked to the syndrome either as a trait or entities mainly linked to metabolic process. Additionally, the latest findings related to the contribution of epigenetic mechanisms, microRNAs, sporadic variants, non-coding RNAs, and assessing the role of genes in molecular systems has enhanced our understanding of the syndrome. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Nonetheless, a common shared genetic cause has not been established to clarify the coexistence of their components and further investigation is required. While mostly neglected and rarely known, hereditary predisposition needs to be studied, including with the current defective phenotypic condition descriptions. Metabolic syndrome is a multi-faceted characteristic with abundant properties and the condition can arise from interactions between environmental variables such as physical inactivity, caloric obesity and genetic susceptibility. Although there is support for genetic determinants from family and twin research, there is still no recognised genomic DNA marker for genetic association and linkages with quite a long way off potential for clinical application. In the present review efforts have been made to through light on the various genetic determinants with large effects that underlie with the association of these traits to this syndrome. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits. [ABSTRACT FROM AUTHOR]

Aim: Uncoupling protein 3 (UCP3) has been identified as a type 2 diabetes (T2D) candidate gene and variant rs1800849 is of potential interest as it is present in the regulatory region of UCP3. The aim of the present candidate gene case-control association study was to evaluate the association of variant rs1800849 of UCP3 with T2D in Mizo population from Northeast India. Methodology: The variation was genotyped using TaqMan allele discrimination assay in 767 individuals (425 cases and 342 healthy controls). Results: The variant rs1800849 of UCP3 was not found to be significantly associated with T2D (p-value = 0.733) in studied population group. Conclusion: Thus, it is concluded that the present study could not replicate the association of variant rs1800849 with genetic susceptibility to T2D in the Mizo population group. This absence of association highlights the genetic heterogeneity prevalent in Indian population groups and warrants screening of other T2D candidate genes in Mizo population group. [ABSTRACT FROM AUTHOR]

Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. In the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D. [ABSTRACT FROM AUTHOR]

Aim: Microtubule actin cross-linking factor 1 (MACF1) has been identified as a type 2 diabetes (T2D) candidate gene, and variant rs2296172 of the gene was found associated with T2D in multiple populations. However, it has never been explored in Mizo population. The aim of the present study was to replicate the association of variant rs2296172 of MACF1 gene with T2D in Mizo population of Northeast India. Methodology: The variation was genotyped using TaqMan allele discrimination assay in 755 individuals (425 cases and 330 healthy controls), belonging to the Mizo population. Results: The variant rs2296172 MACF1 was found to be significantly associated with T2D (p value = 0.001) in Mizo population group with an observed odds ratio of 1.8 [1.3–2.8] at 95% CI after correction with age, gender and BMI. Conclusion: This study is the first replication report from Northeast India, showing variant rs2296172 of MACF1 gene associated with T2D in Mizo population. This independent study highlights MACF1 as a candidate gene for T2D in Asian Indian populations, suggesting it is critical to evaluate the variant rs2296172 in other distinct endogamous Indian population cohorts. [ABSTRACT FROM AUTHOR]

Microtubule actin cross-linking factor 1 (MACF1) gene variant rs2296172 has recently been associated with type 2 diabetes (T2D). However, this variant has never been evaluated as such in Indian populations. In the present replication study, we genotyped variant rs2296172 by Taqman allele discrimination assay in 432 individuals belonging to the Bania caste group from Punjab, India. The single-nucleotide polymorphism (SNP) was evaluated for association with T2D, in a population based candidate gene case-control association study design, by estimating odds ratio with 95% confidence interval. The SNP rs2296172 of MACF1 was found to be significantly associated with T2D (p = 0.02) and odds ratio (OR) = 1.59 (1.06-2.38) at 95% CI. We further emphasize that the Indian population as such is a conglomeration of various endogamous population groups. It is critical that such replication studies be carried out in various populations to find association of variants to T2D susceptibility and understand genetic heterogeneity. However, it is important to avoid pooling of samples to address the concern of population stratification. [ABSTRACT FROM AUTHOR]

Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS-associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 × 10−10; odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 × 10−14; OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS. [ABSTRACT FROM AUTHOR]

Many major rival models of the origin of the Hindu caste system co-exist despite extensive studies, each with associated genetic evidences. One of the major factors that has still kept the origin of the Indian caste system obscure is the unresolved question of the origin of Y-haplogroup R1a1*, at times associated with a male-mediated major genetic influx from Central Asia or Eurasia, which has contributed to the higher castes in India. Y-haplogroup R1a1* has a widespread distribution and high frequency across Eurasia, Central Asia and the Indian subcontinent, with scanty reports of its ancestral (R*, R1* and R1a*) and derived lineages (R1a1a, R1a1b and R1a1c). To resolve these issues, we screened 621 Y-chromosomes (of Brahmins occupying the upper-most caste position and schedule castes/tribals occupying the lower-most positions) with 55 Y-chromosomal binary markers and seven Y-microsatellite markers and compiled an extensive dataset of 2809 Y-chromosomes (681 Brahmins, and 2128 tribals and schedule castes) for conclusions. A peculiar observation of the highest frequency (up to 72.22%) of Y-haplogroup R1a1* in Brahmins hinted at its presence as a founder lineage for this caste group. Further, observation of R1a1* in different tribal population groups, existence of Y-haplogroup R1a* in ancestors and extended phylogenetic analyses of the pooled dataset of 530 Indians, 224 Pakistanis and 276 Central Asians and Eurasians bearing the R1a1* haplogroup supported the autochthonous origin of R1a1 lineage in India and a tribal link to Indian Brahmins. However, it is important to discover novel Y-chromosomal binary marker(s) for a higher resolution of R1a1* and confirm the present conclusions.Journal of Human Genetics (2009) 54, 47–55; doi:10.1038/jhg.2008.2; published online 9 January 2009 [ABSTRACT FROM AUTHOR]

The recent observations that Peroxisome proliferator activated receptor gamma coactivator 1 alpha ( PGC1A) is responsible for the induction of reactive oxygen species (ROS) detoxifying agents and that ROS triggers insulin resistance, support the role that this gene could play in the onset of Type 2 diabetes mellitus (T2DM). Two PGC1A variants Thr394Thr (rs2970847) and Gly482Ser (rs8192673) were genotyped in 822 subjects (351 T2DM cases and 471 controls) from two North Indian populations, represented as Group 1 (Kashmir population) and Group 2 (Punjab and Jammu population). Both Groups 1 and 2 showed a significant association of Thr394Thr variant with T2DM after applying Bonferroni corrections ( P = 0.001 and 0.012, respectively). Logistic regression analysis for Thr394Thr susceptible genotypes together (rs2970847 G/A and A/A) conferred a 1.89-(95%CI 1.25–2.85) fold higher risk for T2DM in Group 1 and 1.81-(95%CI 1.19–2.78) fold risk in Group 2. The susceptible, Ser482 (rs8192673 G/A and A/A) genotypes, gave a 2.04 (95%CI 1.47–3.03) fold higher risk for T2DM in Group 1. Mitochondrial genotype backgrounds observed in association with T2DM (Bhat et al. ), when studied in combination with PGC1A variants, showed an increased prevalence in controls with mt10398G and 16189T along with G/G genotype background at the two polymorphic loci of PGC1A. These observations suggest that the two genotype backgrounds together could provide protection against T2DM. [ABSTRACT FROM AUTHOR]

The role of mitochondria in causing diseases is becoming evident as more and more studies are focusing on this organelle of the cell. This is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes, ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of a mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to T16189C variant is worth addressing as genetic susceptibility factors in type 2 diabetes mellitus (T2DM). A case control study on 312 T2DM cases and ethnically matched 466 controls involving two North Indian populations, referred as cohort 1 and cohort 2 (in a replicative study), was undertaken to test such a genetic association. A statistically significant association was observed for 10398A allele in both the cohorts [cohort1 (OR = 2.67 95% CI 1.77–4.00); cohort2 (OR = 1.76 95%CI 1.12–2.77)]. The analysis of G10398A/T16189C haplotypic combinations revealed that 10398A/16189C haplotype provides a risk in both the cohorts. To sum up the study suggests that 10398A and 16189C alleles provide susceptiblity to T2DM independently as well as together. [ABSTRACT FROM AUTHOR]

The minor haplotype −3575A/-2849G/-2763C in IL-10 promoter has been defined as a marker of disease resistance to leprosy and its severity in Brazilian population. Our investigation of six single-nucleotide polymorphisms (SNPs) in IL-10 promoter in 282 Indian leprosy patients and 266 healthy controls by direct PCR sequencing, however, showed that the extended haplotype: −3575T/-2849G/-2763C/-1082A/-819C/-592C was associated with resistance to leprosy per se and to the development of severe form of leprosy, using either a binomial (controls vs cases, P=0.01, OR=0.58, CI=0.37–0.89) or ordinal (controls vs paucibacillary vs multibacillary, P=0.004) model. Whereas, IL-10 haplotype −3575T/-2849G/-2763C/-1082A/-819T/-592A was associated with the risk of development of severe form of leprosy ( P=0.0002) in contrast to the minor risk haplotype −3575T/-2849A/-2763C in the Brazilian population. The role of IL-10 promoter SNPs in Brazilian and Indian population strongly suggests the involvement of IL-10 locus in the outcome of leprosy. [ABSTRACT FROM AUTHOR]

We have analysed the hypervariable regions (HVR I and II) of human mitochondrial DNA (mtDNA) in individuals from Uttar Pradesh (UP), Bihar (BI) and Punjab (PUNJ), belonging to the Indo-European linguistic group, and from South India (SI), that have their linguistic roots in Dravidian language. Our analysis revealed the presence of known and novel mutations in both hypervariable regions in the studied population groups. Median joining network analyses based on mtDNA showed extensive overlap in mtDNA lineages despite the extensive cultural and linguistic diversity. MDS plot analysis based on Fst distances suggested increased maternal genetic proximity for the studied population groups compared with other world populations. Mismatch distribution curves, respective neighbour joining trees and other statistical analyses showed that there were significant expansions. The study revealed an ancient common ancestry for the studied population groups, most probably through common founder female lineage(s), and also indicated that human migrations occurred (maybe across and within the Indian subcontinent) even after the initial phase of female migration to India. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Four binary polymorphisms and four multiallelic short tandem repeat (STR) loci from the nonrecombining region of the human Y-chromosome were typed in different Indian population groups from Uttar Pradeh (UP), Bihar (BI), Punjab (PUNJ), and Bengal (WB) speaking the Indo-Aryan dialects and from South India (SI) with the root in the Dravidian language. We identified four major haplogroups [(P) 1+, (C and F) 2+, (R1a) 3, (K) 26+] and 114 combinations of Y-STR haplotypes. Analyses of the haplogroups indicated no single origin from any lineage but a result of a conglomeration of different lineages from time to time. The phylogenetic analyses indicate a high degree of population admixture and a greater genetic proximity for the studied population groups when compared with other world populations. [ABSTRACT FROM AUTHOR]

A correction to the article "PGC-1α Thr394Thr and Gly482Ser Variants are Significantly Associated With T2DM in Two North Indian Populations: A Replicate Case-Control Study" is presented.