The Association between Fasting Glucose and Sugar Sweetened Beverages Intake Is Greater in Latin Americans with a High Polygenic Risk Score for Type 2 Diabetes Mellitus

Chile has the highest per capita intake of sugar-sweetened beverages (SSB) world-wide. However, it is unknown whether the effects from this highly industrialized food will mimic those reported in industrialized countries or whether they will be modified by local lifestyle or population genetics. Our goal was to evaluate the association between SSB intake and fasting glucose in the Chilean population. We calculated a weighted genetic risk score (GRSw) based on 16 T2D risk SNPs in 2828 non-diabetic participants of the MAUCO cohort. SSB intake was categorized in four levels using a food frequency questionnaire. Log-fasting glucose was regressed on SSB and GRSw tertiles while accounting for socio-demography, lifestyle, obesity, and Amerindian ancestry. Fasting glucose increased systematically per unit of GRSw (β = 0.02 ± 0.006, p = 0.00002) and by SSB intake (β[cat4] = 0.04 ± 0.009, p = 0.0001), showing a significant interaction, where the strongest effect was observed in the highest GRSw-tertile and in the highest SSB consumption category (β = 0.05 ± 0.02, p = 0.02). SNP-wise, SSB interacted with additive effects of rs7903146 (TCF7L2) (β = 0.05 ± 0.01, p = 0.002) and with the G/G genotype of rs10830963 (MTNRB1B) (β = 0.19 ± 0.05, p = 0.001). Conclusions: The association between SSB intake and fasting glucose in the Chilean population without diabetes is modified by T2D genetic susceptibility.

An Investigation of the Role of Common and Rare Variants in a Large Italian Multiplex Family of Multiple Sclerosis Patients

Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.

Polygenic Risk for Coronary Artery Disease in the Scottish and English Population

Background: Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. Methods: Studying UK Biobank we assessed CAD risk based on the Framingham risk score (FRS) and common genetic variants to explore the respective contribution to CAD prevalence in Scotland (n=31,963) and England (n=317,889). We calculated FRS based on sex, age, body mass index, total cholesterol, high density lipoprotein cholesterol, systolic blood pressure, antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk.Results: Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P<0.001). By contrast, the FRS predicted a less than 1% higher CAD risk in Scotland (12.5±10.5 vs.12.6±10.6, P=0.03). Likewise, the overall number genome-wide significant variants affecting CAD risk (157.6±7.7 and 157.5±7.7; P=0.12) and a wGRS for CAD (2.49±0.25 in both populations, P=0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences with respect to the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here 35 had higher frequencies in Scotland whereas 37 had higher frequencies in England (P<0.001 each).Conclusions: Neither the traditional risk factors included in the FRS nor a GRS based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.

1625 Genome-Wide Association Analysis and Replication In 810,625 Individuals Identifies Novel Therapeutic Targets for Varicose Veins

Aim To elucidate the genetic architecture of varicose veins (VVs) and identify genes and biological pathways central to their pathobiology. Method We performed hitherto the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe, Inc (total 135,514 VVs cases and 675,111 controls). Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for VVs was constructed to compare genetic susceptibility in surgical vs non-surgical VVs patients. Results 109 genome-wide significant (P ≤ 5 × 10-8) loci were identified in UK Biobank, 46 of which successfully replicated in the 23andMe cohort. Twenty-eight loci have not been previously reported. We mapped 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis. The wGRS analysis demonstrated that VVs patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 2.46 × 10−13). Conclusions This study has advanced our understanding of VVs pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to VVs.

1540 Genome-Wide Association Analysis In 401,583 Individuals Identifies Novel Therapeutic Targets for Haemorrhoids

Aim To elucidate the genetic architecture of haemorrhoids and identify genes and biological pathways central to their pathobiology. Method We report the first ever genome-wide association study of haemorrhoids in 31,652 cases and 369,931 controls from UK Biobank. Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for haemorrhoids was constructed to compare genetic susceptibility in surgical vs non-surgical haemorrhoids patients. Results Twelve novel genome-wide significant susceptibility loci were discovered to be associated with haemorrhoids. Seventeen genes were mapped to these loci, and gene sets in biological pathways relating to extracellular matrix regulation and TGF-β signalling were strongly implicated. Seven gene-products (41.2%) were predicted tractable to antibody and/or small molecule targeting, and three products (17.6%) have known pharmaceutical interactions (ACHE, ADRA2B, ELN). The wGRS analysis demonstrated that haemorrhoid patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 4.58 × 10-27). Conclusions This study has advanced our understanding of haemorrhoids pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to haemorrhoids.

Genome-wide gene-air pollution interaction analysis of lung function in 300,000 individuals

Impaired lung function is predictive of mortality and is a key component in the diagnosis of chronic obstructive pulmonary disease. Lung function has a strong genetic component but is also affected by environmental factors such as increased exposure to air pollution. How genetic factors and air pollution interact to affect lung function is however less understood. We conducted a genome-wide gene-air pollution interaction analysis of spirometry measures with three measures of air pollution at home address: particulate matter (PM2.5 & PM10) and nitrogen dioxide (NO2), in approximately 300,000 unrelated European individuals from UK Biobank. We explored air pollution interactions with previously identified lung function signals and determined their combined interaction effect using a polygenic risk score (PRS). We identified seven genome-wide interaction signals (P < 5 x 10 -8), and a further ten suggestive interaction signals (P < 5 x 10 -7). We found statistical evidence of interaction with PM2.5 for previous lung function signal, rs10841302, near AEBP2, suggesting increased susceptibility of FEV1/FVC to PM2.5, as copies of the G allele increased (interaction beta: -0.073 percentage points, 95%CI: -0.105,-0.041). There was no observed interaction between air pollutants and the weighted genetic risk score. We carried out the largest genome-wide gene-air pollution interaction study of lung function and identified effects of clinically relevant size and significance. We observed up to 440ml lower lung function for certain genotypes associated with mean levels of outdoor air pollution at baseline, which is approximately equivalent to nine years of normal loss of lung function.

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.

Genome-wide and candidate gene association analyses identify a 14-SNPs combination for hypertension in patients with type 2 diabetes

Background High blood pressure is common and comorbid with type 2 diabetes (T2D). Almost 50% of patients with T2D have high blood pressure. Patients with both conditions of hypertension and T2D are at risk for cardiovascular diseases and mortality. The study aim was to investigate genetic risk factors for hypertension in T2D patients. Methods This study included 999 T2D (cohort 1) patients for the first genome scan stage and 922 T2D (cohort 2) patients for the replication stage. Here, we investigated the genetic susceptibility and cumulative weighted genetic risk score for hypertension in T2D patients of Han Chinese descent in Taiwan. Results Thirty novel genetic single nucleotide polymorphisms (SNPs) were associated with hypertension in T2D after adjusting for age and body mass index (p-value &lt; 1 x10 -4). Eight blood pressure-related and/or hypertension-related genetic SNPs were associated with hypertension in T2D after adjusting for age and body mass index (p-value &lt; 0.05). Linkage disequilibrium (LD) and cumulative weighted genetic risk score analyzes showed that 14 of the 38 SNPs were associated with risk of hypertension in a dose-dependent manner in T2D (Cochran-Armitage trend test: p-value &lt; 0.0001). The 14-SNPs cumulative weighted genetic risk score was also associated with increased regression tendency of systolic blood pressure in T2D (SBP = 122.05 + 0.8 x weighted GRS; p-value = 0.0001). Conclusions A cumulative weighted genetic risk score composed of 14 SNPs is important for hypertension, increased tendency of systolic blood pressure, and may contribute to hypertension risk in T2D in Taiwan.

Genome-wide meta-analysis reveals novel susceptibility loci for thyrotoxic periodic paralysis

Objective Thyrotoxic periodic paralysis (TPP) is a rare and potentially fatal complication of hyperthyroidism. By meta-analysis of genome-wide association studies, we aim to discover novel susceptibility loci and understand the pathogenesis of TPP. Methods This meta-analysis comprised 319 TPP cases and 3516 healthy controls from three independent cohorts (two from Hong Kong; one from Shanghai). Genetic variants in each cohort were separately genotyped, imputed and analyzed for association with TPP. Fixed-effect meta-analysis was performed to combine the data. Using the three independent genome-wide significant variants, a weighted genetic risk score (GRS) was developed. Results Of 7 077 246 variants tested for association with TPP, 260 variants reached genome-wide significance and were represented by independent variants from four distinct genomic loci, but a risk locus for Graves’ disease at 6p21.33–p21.22 was excluded from subsequent analyses. Two novel loci near TRIM2 (4q31.3; rs6827197: OR = 4.075; P = 3.46 × 10−9) and AC140912.1 (16q22.3; rs6420387: OR = 1.861; P = 2.66 × 10−8) were identified. Together with previously reported KCNJ2 (17q24.3; rs312743: OR = 2.564; P = 1.15 × 10−21), the three susceptibility variants explained 4.36% of the genetic liability. Expression quantitative trait loci analyses showed the variants altered expression of TRIM2 in nerve and KCNJ2 in skeletal muscle. The weighted GRS had an area under curve of 0.827 and 0.682 in the derivation and validation cohorts in Hong Kong. Conclusions We identified two novel TPP risk loci near TRIM2 and AC140912.1. While rare mutations in TRIM2 and KCNJ2 were implicated in monogenic disorders characterized by muscle paralysis, our study suggested common variants near these genes might dysregulate gene expression and lead to milder phenotypes.