The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

Background: The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. \ud \ud Methods: We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. \ud \ud Results: Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). \ud \ud Conclusion: This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group. \ud \ud Trial registration: UKADS Trial Registration: ISRCTN38297969

Quantification of diabetes comorbidity risks across life using nation-wide big claims data

Despite substantial progress in the study of diabetes, important questions remain about its comorbidities and clinical heterogeneity. To explore these issues, we develop a framework allowing for the first time to quantify nation-wide risks and their age- and sex-dependence for each diabetic comorbidity, and whether the association may be consequential or causal, in a sample of almost two million patients. This study is equivalent to nearly 40,000 single clinical measurements. We confirm the highly controversial relation of increased risk for Parkinson's disease in diabetics, using a 10 times larger cohort than previous studies on this relation. Detection of type 1 diabetes leads detection of depressions, whereas there is a strong comorbidity relation between type 2 diabetes and schizophrenia, suggesting similar pathogenic or medication-related mechanisms. We find significan sex differences in the progression of, for instance, sleep disorders and congestive heart failure in diabetic patients. Hypertension is a highly sex-sensitive comorbidity with females being at lower risk during fertile age, but at higher risk otherwise. These results may be useful to improve screening practices in the general population. Clinical management of diabetes must address age- and sex-dependence of multiple comorbid conditions

Conjunct Agreement and Gender in South Slavic: From Theory to Experiments to Theory

Agreement with coordinated subjects in Slavic languages has recently seen a rapid increase in theoretical and experimental approaches, contributing to a wider theoretical discussion on the locus of agreement in grammar (cf. Marušič, Nevins, and Saksida 2007; Bošković 2009; Marušič, Nevins, and Badecker 2015). This paper revisits the theoretical predictions proposed for conjunction agreement in a group of South Slavic languages, with a special focus on gender agreement. The paper is based on two experiments involving speakers of Bosnian/Croatian/Serbian (BCS) and Slovenian (Sln). Experiment 1 is an elicited production experiment investigating preverbal-conjunct agreement, while Experiment 2 investigates postverbal-conjunct agreement. The data provide experimental evidence discriminating between syntax proper and distributed-agreement models in terms of their ability to account for preverbal highest-conjunct agreement and present a theoretical mechanism for the distinction between default agreement (which has a fixed number and gender, independent of the value of each conjunct) and resolved agreement (which computes number and gender based on the values of each conjunct and must resolve potential conflicts). Focusing on the variability in the gender-agreement ratio across nine combinations, the experimental results for BCS and Sln morphosyntax challenge the notion of gender markedness that is generally posited for South Slavic languages

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

When linearity prevails over hierarchy in syntax

Hierarchical structure has been cherished as a grammatical universal. We use experimental methods to show where linear order is also a relevant syntactic relation. An identical methodology and design were used across six research sites on South Slavic languages. Experimental results show that in certain configurations, grammatical production can in fact favor linear order over hierarchical structure. However, these findings are limited to coordinate structures and distinct from the kind of production errors found with comparable configurations such as “attraction” errors. The results demonstrate that agreement morphology may be computed in a series of steps, one of which is partly independent from syntactic hierarchy

Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants?

AIMS/HYPOTHESIS: According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci. METHODS: We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F (ST)) for 17 type 2 diabetes and 13 obesity loci. RESULTS: We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F (ST) for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date. CONCLUSIONS/INTERPRETATION: Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues

A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations