Bratati Kahali

Population genetic differentiation of height and body mass index across Europe

Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10−8; BMI, P < 5.95 × 10−4), and we find an among-population genetic correlation for tall and slender individuals (r = −0.80, 95% CI = −0.95, −0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

Characterization of european ancestry nonalcoholic fatty liver disease-associated variants in individuals of african and hispanic descent

Nonalcoholic fatty liver disease (NAFLD) is an obesity‐related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African‐ and/or Hispanic‐Americans and fine‐mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African American (n = 3,124) and one Hispanic American (n = 849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta‐analyzed. Fine‐mapping across African American cohorts was conducted using meta‐analysis. African‐ and Hispanic‐American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9 kg/m2, respectively. Hepatic steatosis was 0.20‐0.34 heritable in African‐ and Hispanic‐American families (P < 0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine‐mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1. Conclusion: Multiple genetic variants are associated with hepatic steatosis across ancestries. This explains a substantial proportion of the genetic predisposition in African‐ and Hispanic‐Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries. (Hepatology 2013;53:966–975)

Mendelian randomization study of body mass index and colorectal cancer risk

Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.

TM6SF2: Catch-22 in the Fight Against Nonalcoholic Fatty Liver Disease and Cardiovascular Disease?

onalcoholic fatty liver disease N(NAFLD) is rapidly becoming the most common cause of chronic liver disease worldwide. NAFLD includes a spectrum of disease ranging from the accumulation of fat in the liver (steatosis) to histologic evidence of necroinflammation (nonalcoholic steatohepatitis [NASH]), then fibrosis and cirrhosis, in the absence of excessive alcohol ingestion. Approximately one-third of the US population has radiologic evidence of NAFLD. Although the majority (70%–90%) will have relatively benign simple steatosis, NAFLD may progress to cirrhosis or hepatocellular carcinoma, and can lead to liver failure in the absence of lifestyle change or effective pharmacological treatments. Although morbidity and mortality from liver disease are increased greatly in patients with NAFLD, morbidity and mortality from cardiovascular disease is even more prevalent in this population. NAFLD, a complex trait influenced by interpatient genetic variations and environmental influences, is widely considered to be the hepatic manifestation of the metabolic syndrome. It correlates epidemiologically with the presence of features of the metabolic syndrome, which consists of having 3 of the following: impaired fasting glucose, central obesity, dyslipidemia (low high-density lipoprotein cholesterol, high low-density lipoprotein [LDL], or both) and hypertension. There is substantial interpatient variation in which features of the metabolic syndrome are exhibited, and which clinical sequelae an individual may develop. In some cases the metabolic syndrome predisposes to NAFLD and in others to cardiovascular disease. Determining why this occurs is critical to making clinical recommendations based on personal rather than population risk. Although the exact cause of NAFLD or NASH has not been elucidated, we are now able to begin to understand the genetic basis for the disease. NAFLD clusters in families, and its heritability is estimated to be 26%– 27% for CT-measured hepatic steatosis. Genome-wide association studies (GWAS) and candidate gene studies have provided important insights into the genetic contribution to NAFLD. The nonsynonymous single nucleotide polymorphism (SNP), rs738409 (c.444 C>G, I148M) in patatin-like phospholipase domaincontaining 3 (PNPLA3) was associated significantly with H-magnetic resonance spectroscopy measured hepatic triglyceride (TG) content and has subsequently been validated globally as a major genetic determinant of not only steatosis, but also severity of NASH, stage of hepatic fibrosis/ cirrhosis, and occurrence of NAFLDassociated HCC. The largest GWAS meta-analysis for NAFLD to date, using 2.4 million SNPs imputed to HapMap in 7176 individuals of European ancestry, identified common variants at 5 loci. These variants are in or near the genes PNPLA3, GCKR, LYPLAL1, and PPP1R3B, and a region on chromosome 19 (19p13.11) that contains multiple genes and has variously been called NCAN/TM6SF2/ CILP2/PBX4 in the literature. The variants at most of these loci are also associated with NASH/fibrosis (all but those at PPP1R3B). Variants at the PNPLA3 locus conferred the strongest effect, predisposing to advanced liver disease with an odds ratio (OR) of 3.26 (95% CI, 2.11–7.21), with the variants at the 19p13.11 locus being the second strongest at 1.65 (95% CI, 1.15–2.65) per mutant allele. The PNPLA3 and chromosome 19p13.11 locus also associated with histologic NASH/fibrosis in an independent sample of bariatric surgery patients. Interestingly, NAFLDassociated variants did not result in uniform abnormalities of serum lipids or glycemic and anthropometric traits. In particular, variants at the chromosome 19p13.11 locus associated with increased hepatic steatosis/ NASH/fibrosis were also associated with decreased serum LDL cholesterol and lower serum TGs, which was contrary to the usually observed epidemiologic pattern of these traits. Variants at 19p13.11 were not associated significantly with serum glucose or measures of insulin resistance in the best powered analyses at the time. Variants at PNPLA3 and LYPLAL1 did not affect serum lipid or glycemic traits, whereas those at GCKR and PPP1R3B were associated with increased serum LDL cholesterol and lower serum glucose levels. These results suggested a heterogeneous etiology to NAFLD and the existence of multiple genetic metabolic disease “subtypes” that may require more precision treatment in the future. Work from several groups has now extended these findings. It has recently been reported that a nonsynonymous genetic variant within a gene of unknown function called TM6SF2, transmembrane 6 superfamily member 2, (rs58542926 c.449 C>T) at the 19p13.11 locus was associated with hepatic steatosis in 2,736 individuals genotyped using a human exome chip. This variant is in strong linkage disequilibrium (r 1⁄4 0.798) with variants in the chromosome 19p13.11 locus previously reported to be NAFLD risk factors, making it likely that the new and old signals are the same. Indeed, conditional analyses indicate that TM6SF2 rs58542926 may be the causal variant driving the association at this locus. The TM6SF2 rs58542926 variant has subsequently been associated with severity of NAFLD-associated hepatic fibrosis/ cirrhosis (OR, 1.88 [95% CI, 1.41–2.5] for advanced fibrosis per each copy of the minor allele carried), independent of confounding factors including age, diabetes, obesity, or PNPLA3 genotype, in a cohort of >1000 histologically characterized patients, consistent with previous associations at this

Evolutionary constraints on hub and non-hub proteins in human protein interaction network: Insight from protein connectivity and intrinsic disorder

It has been claimed that proteins with more interacting partners (hubs) are structurally more disordered and have a slow evolutionary rate. Here, in this paper we analyzed the evolutionary rate and structural disorderness of human hub and non-hub proteins present/absent in protein complexes. We observed that both non-hub and hub proteins present in protein complexes, are characterized by high structural disorderness. There exists no significant difference in average evolutionary rate of complex-forming hub and non-hub proteins while we have found a significant difference in the average evolutionary rate between hub and non-hub proteins which are not present in protein complexes. We concluded that higher disorderness in complex forming non-hub proteins facilitates higher number of interactions with a large number of protein subunits. High interaction among protein subunits of complex forming non-hub proteins imposes a selective constraint on their evolutionary rate.

Exploring the evolutionary rate differences of party hub and date hub proteins in Saccharomyces cerevisiae protein–protein interaction network

Evolutionary rates of party hub and date hub proteins of Saccharomyces cerevisiae are analyzed under the perspective of ordered/disordered ness of proteins and the three dimensional structural context such as the solvent accessibility of the amino acid residues. Our results suggest that the lowering of evolutionary rate of the party hub proteins than the date hub proteins is solely contributed by the ordered regions of the corresponding proteins. Moreover the slower evolutionary rate of the party hub proteins than the date hub counterparts can be attributed to the presence of buried amino acid residues. Thus, our work endeavors further into the understanding of the evolutionary rate differences of the two different types of hub proteins of S. cerevisiae.

Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.

Protein complex forming ability is favored over the features of interacting partners in determining the evolutionary rates of proteins in the yeast protein-protein interaction networks

BackgroundEvolutionary rates of proteins in a protein-protein interaction network are primarily governed by the protein connectivity and/or expression level. A recent study revealed the importance of the features of the interacting protein partners, viz., the coefficient of functionality and clustering coefficient in controlling the protein evolutionary rates in a protein-protein interaction (PPI) network.ResultsBy multivariate regression analysis we found that the three parameters: probability of complex formation, expression level and degree of a protein independently guide the evolutionary rates of proteins in the PPI network. The contribution of the complex forming property of a protein and its expression level led to nearly 43% of the total variation as observed from the first principal component. We also found that for complex forming proteins in the network, those which have partners sharing the same functional class evolve faster than those having partners belonging to different functional classes. The proteins in the dense parts of the network evolve faster than their counterparts which are present in the sparse regions of the network. Taking into account the complex forming ability, we found that all the complex forming proteins considered in this study evolve slower than the non-complex forming proteins irrespective of their localization in the network or the affiliation of their partners to same/different functional classes.ConclusionsWe have shown here that the functionality and clustering coefficient correlated with the degree of the protein in the protein-protein interaction network. We have identified the significant relationship of the complex-forming property of proteins and their evolutionary rates even when they are classified according to the features of their interacting partners. Our study implies that the evolutionarily constrained proteins are actually members of a larger number of protein complexes and this justifies why they have enhanced expression levels.

Delving deeper into the unexpected correlation between gene expressivity and codon usage bias of Escherichia coli genome.

Abstract Biased usage of synonymous codons has been elucidated under the perspective of cellular tRNA abundance and more recently by the mRNA secondary structure folding stability of the corresponding genes. Taking advantage of publicly available gene expression data for Escherichia coli, a comprehensive investigation of the three classes of genes having different codon usage biases was performed from the standpoint of tRNA abundance, mRNA secondary structure folding stability, and translational error minimization procedure. We detected the different evolutionary forces for translational and/or transcriptional regulation of highly expressed genes depending upon their codon bias. Additionally, the possible role of mRNA folding stability in maintaining the overall high expressivity of the set of lowly biased genes has been articulated. These novel findings certainly strengthen the understanding of the codon usage bias in the Escherichia coli genome.

On nucleotide solvent accessibility in RNA structure.

Sequence dependence of solvent accessibility in globular and membrane proteins is well established. However, this important structural property has been poorly investigated in nucleic acids. On the other hand investigation of structural determinants of transcriptional and post-transcriptional processes in gene expression are also in a primitive stage and there is a need to explore novel sequence and structural features of both DNA and RNA, which may explain both basic and regulatory mechanisms at various stages of expression. We have recently shown that the nucleotide accessibility in double-stranded DNA molecules strongly depends on sequence context and can be predicted using neighbor information. In this work, we investigate statistics, neighbor-dependence and predictability of nucleotide solvent accessibility for various types of RNA molecules (single-stranded, double-stranded, protein-unbound and protein-bound). It was found that average solvent accessibility of different RNA trinucleotides varies considerably. Interestingly, important translational signals (initiatory AUG codon, Shine-Dalgharno site) were characterized by high solvent accessibility that could be important for its selection in evolution. We also analyzed a relationship between nucleotide accessibility and synonymous codon usage bias in some genomes and find that the two properties are directly related. We believe that the analysis and prediction of nucleotide solvent accessibility opens new avenues to explore more biologically meaningful relationship between RNA structure and function.