An Investigation of Genome-Wide Studies Reported Susceptibility Loci for Ulcerative Colitis Shows Limited Replication in North Indians

Genome-Wide Association studies (GWAS) of both Crohn's Disease (CD) and Ulcerative Colitis (UC) have unearthed over 40 risk conferring variants. Recently, a meta-analysis on UC revealed several loci, most of which were either previously associated with UC or CD susceptibility in populations of European origin. In this study, we attempted to replicate these findings in an ethnically distinct north Indian UC cohort. 648 UC cases and 850 controls were genotyped using Infinium Human 660W-quad. Out of 59 meta-analysis index SNPs, six were not in the SNP array used in the study. Of the remaining 53 SNPs, four were found monomorphic. Association (p<0.05) at 25 SNPs was observed, of which 15 were CD specific. Only five SNPs namely rs2395185 (HLA-DRA), rs3024505 (IL10), rs6426833 (RNF186), rs3763313 (BTNL2) and rs2066843 (NOD2) retained significance after Bonferroni correction. These results (i) reveal limited replication of Caucasian based meta-analysis results; (ii) reiterate overlapping molecular mechanism(s) in UC and CD; (iii) indicate differences in genetic architecture between populations; and (iv) suggest that resources such as HapMap need to be extended to cover diverse ethnic populations. They also suggest a systematic GWAS in this terrain may be insightful for identifying population specific IBD risk conferring loci and thus enable cross-ethnicity fine mapping of disease loci

Stratification of rheumatoid arthritis cohort using <i>Ayurveda </i>based deep phenotyping approach identifies novel genes in a GWAS

BACKGROUND AND AIM: Genome wide association studies have scaled up both in terms of sample size and range of complex disorders investigated, but these have explained relatively little phenotypic variance. Of the several reasons, phenotypic heterogeneity seems to be a likely contributor for missing out genetic associations of large effects. Ayurveda, the traditional Indian system of medicine is one such tool which adopts a holistic deep phenotyping approach and classifies individuals based on their body constitution/prakriti. We hypothesized that Ayurveda based phenotypic stratification of healthy and diseased individuals will allow us to achieve much desired homogeneous cohorts which would facilitate detection of genetic association of large effects. In this proof of concept study, we performed a genome wide association testing of clinically diagnosed rheumatoid arthritis patients and healthy controls, who were re-phenotyped into Vata, Pitta and Kapha predominant prakriti sub-groups. EXPERIMENTAL PROCEDURE: Genotypes of rheumatoid arthritis cases (Vata = 49; Pitta = 117; Kapha = 78) and controls (Vata = 33; Pitta = 175; Kapha = 85) were retrieved from the total genotype data, used in a recent genome-wide association study performed in our laboratory. A total of 528461 SNPs were included after quality control. Prakriti-wise genome-wide association analysis was employed. RESULTS AND CONCLUSION: This study identified (i) prakriti-specific novel disease risk genes of high effect sizes; (ii) putative candidates of novel therapeutic potential; and (iii) a good correlation between genetic findings and clinical knowledge in Ayurveda. Adopting Ayurveda based deep phenotyping may facilitate explaining hitherto undiscovered heritability in complex traits and may propel much needed progress in personalized medicine

List of significant (p<0.05) SNPs in and around IL23R gene.

<p>List of significant (p<0.05) SNPs in and around IL23R gene.</p

Enrichment of Lactic Acid-Producing Bacteria in the Fecal Microbiota of Patients with Ulcerative Colitis in North India

Previous studies have established the relationship between the gut microbiota and ulcerative colitis (UC); however, there is a scarcity of data on the fecal microbiome profile of patients with UC in the Indian population. This study aimed to examine the fecal microbiome profile of north Indian patients with UC (n=105), including with active disease (n=64) and in remission (n=41), compared to healthy controls (n=36), using 16S rRNA gene sequencing. Both relative abundance analysis and linear discriminant analysis effect size (LEfSe) revealed a significant enrichment of lactic acid-producing facultative anaerobic pathobionts, namely, Bifidobacterium, Lactobacillus, and Streptococcus, in patients with UC (both with active disease and those in remission). Additionally, a significant decrease was observed in anaerobic genera responsible for the synthesis of short-chain fatty acids (SCFAs), especially butyrate, such as Blautia, Roseburia, Lachnospiraceae, and Ruminococcaceae. Differential metabolic pathway analysis using PICRUSt2 confirmed a loss of SCFAs production and increased lactose and nitrate metabolism in UC patients. Biochemical analysis of fecal samples confirmed the increased colonization of nitrate-reducing microbes in UC patients, suggesting inflammation-driven dysbiosis. LEfSe and PICRUSt2 analyses revealed an enrichment of Prevotella and Blautia microbes and the upregulation of two specific metabolic pathways, sulfolactate degradation and reductive acetyl coenzyme A pathway-I, which can distinguish UC patients in remission from those with active disease. Our findings caution against the use of lactic acid-producing bacteria (LABs) and recommend the exploration of butyrate-producing microbes as probiotics to restore SCFAs levels in UC patients

Population and genomic lessons from genetic analysis of two Indian populations

Indian demographic history includes special features such as founder effects, interpopulation segregation, complex social structure with a caste system and elevated frequency of consanguineous marriages. It also presents a higher frequency for some rare mendelian disorders and in the last two decades increased prevalence of some complex disorders. Despite the fact that India represents about one-sixth of the human population, deep genetic studies from this terrain have been scarce. In this study, we analyzed high-density genotyping and whole-exome sequencing data of a North and a South Indian population. Indian populations show higher differentiation levels than those reported between populations of other continents. In this work, we have analyzed its consequences, by specifically assessing the transferability of genetic markers from or to Indian populations. We show that there is limited genetic marker portability from available genetic resources such as HapMap or the 1,000 Genomes Project to Indian populations, which also present an excess of private rare variants. Conversely, tagSNPs show a high level of portability between the two Indian populations, in contrast to the common belief that North and South Indian populations are genetically very different. By estimating kinship from mates and consanguinity in our data from trios, we also describe different patterns of assortative mating and inbreeding in the two populations, in agreement with distinct mating preferences and social structures. In addition, this analysis has allowed us to describe genomic regions under recent adaptive selection, indicating differential adaptive histories for North and South Indian populations. Our findings highlight the importance of considering demography for design and analysis of genetic studies, as well as the need for extending human genetic variation catalogs to new populations and particularly to those with particular demographic histories.International fellowship funded by Center for Neurogenomics and Cognitive Research (CNCR), VU, Amsterdam, The Netherlands to GJ; Research grant from J C Bose fellowship to BKT; grant # BT/01/COE/07/UDSC to BKT and salary support to GJ are gratefully acknowledged. FC was supported by a Beatriu de Pinós (2010-BP- B-00128) fellowship and MM by a PhD grant both from AGAUR (Generalitat de Catalunya). Funding to FC by grant SAF2012-35025 from the Ministerio de Economía y Competitividad (Spain); Funding to JB by grants BFU2010-19443 from the Ministerio de Ciencia y Tecnología (Spain), PRI-PIBIN-2011-0942 from the Ministerio de Economía y Competitividad (Spain), and from the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101).Peer Reviewe

Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis

Objective Over 100 ulcerative colitis (UC) loci have been identified by genome-wide association studies (GWASs) primarily in Caucasians (CEUs). Many of them have weak effects on disease susceptibility, and the bulk of the heritability cannot be ascribed to these loci. Very little is known about the genetic background of UC in non-CEU groups. Here we report the first GWAS on UC in a genetically distinct north Indian (NI) population

Limited Evidence for Parent-of-Origin Effects in Inflammatory Bowel Disease Associated Loci

Background: Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only similar to 23% of the genetic risk. Part of the 'hidden heritability' could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients. Methods: We selected 28 genetic loci associated with both CD and UC, and tested them for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci. Results: We identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03). Conclusions: Little is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further