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Valvular heart disease is associated with a high global burden of disease. Even mild aortic stenosis confers increased morbidity and mortality, prompting interest in understanding normal variation in valvular function at scale.We developed a deep learning model to study velocity-encoded magnetic resonance imaging in 47,223 UK Biobank participants. We calculated eight traits, including peak velocity, mean gradient, aortic valve area, forward stroke volume, mitral and aortic regurgitant volume, greatest average velocity, and ascending aortic diameter. We then computed sex-stratified reference ranges for these phenotypes in up to 31,909 healthy individuals. In healthy individuals, we found an annual decrement of 0.03cm2in the aortic valve area. Participants with mitral valve prolapse had a 1 standard deviation [SD] higher mitral regurgitant volume (P=9.6 × 10−12), and those with aortic stenosis had a 4.5 SD-higher mean gradient (P=1.5 × 10−431), validating the derived phenotypes’ associations with clinical disease. Greater levels of ApoB, triglycerides, and Lp(a) assayed nearly 10 years prior to imaging were associated with higher gradients across the aortic valve. Metabolomic profiles revealed that increased glycoprotein acetyls were also associated with an increased aortic valve mean gradient (0.92 SD, P=2.1 x 10−22). Finally, velocity-derived phenotypes were risk markers for aortic and mitral valve surgery even at thresholds below what is considered relevant disease currently.Using machine learning to quantify the rich phenotypic data of the UK Biobank, we report the largest assessment of valvular function and cardiovascular disease in the general population.

Background: As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease. Objectives: In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. Methods: We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants. Results: Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores. Conclusions: Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.

Gene expression causally contributes to phenotypic variability. However, since tissue-specific gene expression is difficult to measure at scale, inferring phenotypic risk for individuals using expression profiles can be difficult. We statistically imputed tissue-specific gene expression for 486,452 UK Biobank participants and demonstrated its applications using rich phenotypic data in the biorepository. We performed joint analysis of transcriptome-wide association studies (TWAS) and colocalization for six traits to prioritize tissue-gene pairs for therapeutics development. Using genes identified in TWAS, we constructed imputed transcriptome risk scores and showed their predictive utility even when conditioning on genome-wide polygenic risk scores. A phenome-wide association analysis for established therapeutic targets in whole blood recapitulated known biology and prioritized repurposing potentials supported by previous literature. Our study provides evidence supporting the utility of individual-level imputed transcriptomes for discovering novel gene-tissue-phenotype trios, expression-based phenotypic risk prediction, and identifying individuals with therapeutically targetable predisposition to disease.

The impact of genetic variation on overall disease burden has not been comprehensively evaluated. We introduce an approach to estimate the effect of genetic risk factors on disability-adjusted life years (DALYs; 'lost healthy life years'). We use genetic information from 735,748 individuals and consider 80 diseases. Rare variants had the highest effect on DALYs at the individual level. Among common variants, rs3798220 (LPA) had the strongest individual-level effect, with 1.18 DALYs from carrying 1 versus 0 copies. Being in the top 10% versus the bottom 90% of a polygenic score for multisite chronic pain had an effect of 3.63 DALYs. Some common variants had a population-level effect comparable to modifiable risk factors such as high sodium intake and low physical activity. Attributable DALYs vary between males and females for some genetic exposures. Genetic risk factors can explain a sizable number of healthy life years lost both at the individual and population level.

Background The phospholipase domain-containing 3 gene (PNPLA3)-148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride-rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride-rich very-low-density lipoprotein (VLDL), (VLDL1), and smaller VLDL2 in homozygotes for the PNPLA3-148M variant. Methods and results The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3-148M and nine subjects homozygous for PNPLA3-148I (controls). Liver fat was >3-fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL1 did not differ significantly between the two groups. Likewise, production rates for VLDL2-apoB100 and -triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL1 and VLDL2, were not significantly different. Conclusions Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects.

Inflammatory and infectious upper respiratory diseases (IURDs; ICD-10: J30-J39), such as diseases of sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyzed genome-wide association to eight IURDs (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. We aimed to understand which genetic loci contribute to susceptibility to IURDs in general and its subtypes. We detected 59 independent genome-wide significant (GWS) loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine-mapping implicated non-synonymous variants in 16 genes, including 10 linked to immune-related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal disease loci and inflammatory bowel diseases, and other immune-mediated disorders at pharyngeal disease loci. IURDs also genetically correlated with autoimmune diseases such as rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological reaction. We show shared heritability among IURDs that extends to several immune-mediated diseases with diverse mechanisms, such as type 2 high inflammation.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood and treatment options are limited. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 2,413 cases and 762,382 controls. We identify 15 novel risk loci (p < 5*10−8) and replicate the regions of RELN and two previously reported candidate genes (TGFB1 and MEPE). Implicated genes in many loci are essential for bone remodelling or mineralization. Otosclerosis is genetically correlated with height and fracture risk, and the association loci overlap with severe skeletal disorders. Our results highlight TGFβ1 signalling for follow-up mechanistic studies.

Supplemental Digital Content is available in the text., Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.

While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85–12.58 g, p = 2.3 × 10–58). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66–2.01, p = 1.6 × 10–36). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26–1.99, p = 8.2 × 10–5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20–1.47, p = 4.5 × 10–8) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.

BackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95thpercentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low‐density lipoprotein cholesterol ( LDL ‐C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population‐based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first‐degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL ‐C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta‐analysis of the hyperlipidemic families and the population cohort (high LDL ‐C: hazard ratio, 1.74 [95% CI, 1.48–2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09–1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid‐lowering medication. In lipidomic profiling, high LDL ‐C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P ‐value range 0.038–2.3×10 −56 ). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL ‐C: r =0.80; triacylglycerides: r =0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population‐based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL ‐C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population‐ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

ObjectiveTo develop a highly polygenic risk score (PRS) for alcohol consumption and study whether it predicts alcohol-related morbidity and all-cause mortality.DesignBiobank-based prospective cohort studySettingFinnGen Study (Finland)Participants96,499 genotyped participants from the nationwide prospective FinnGen study and 36,499 participants from prospective cohorts (Health 2000, FINRISK, Twin Cohort) with detailed baseline data and up to 25 years of follow-up time.Main outcome measuresIncident alcohol-related morbidity and alcohol-related or all-cause mortality, based on hospitalizations, outpatient specialist care, drug purchases, and death reports.ResultsIn 96,499 FinnGen participants there were in total 4,785 first-observed incident alcohol-related health events. The PRS of alcohol consumption was associated with alcohol-related morbidity and the risk estimate (hazard ratio, HR) between the highest and lowest quintiles of the PRS was 1.67 [ 95 % confidence interval: 1.52-1.84], p=3.2*10−27). In 28,639 participants with comprehensive baseline data from prospective Health 2000 and FINRISK cohorts, 911 incident first alcohol-related events were observed. When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI=[1.26-1.99], p=8.2*10−5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI=[1.2-1.47], p=4.5e-08) in the adjusted model. In all 39,695 participants with self-reported alcohol consumption available, a 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (β=11.2 [9.85-12.58 g], p = 2.3*10−58).ConclusionsThe PRS for alcohol consumption associates for both alcohol-related morbidity and all-cause mortality. These findings underline the importance of heritable factors in alcohol-related behavior and the related health burden. The results highlight how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.

Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r(g)) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference >= 3 kg/m(2)). Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r(g) = 0.40), glycoprotein (r(g) = 0.37), serum triglycerides (r(g) = 0.36), BCAAs (r(g) = 0.30-0.40), HDL particle diameter (r(g) = -0.33) and HDL cholesterol (r(g) = -0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. (C) 2015 Elsevier Inc. All rights reserved.

AimGenetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures.Methods and ResultsWe performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical endpoints related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P−8), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92).ConclusionOur study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.

Aims: To characterize and compare coronary artery disease (CAD) risk and detailed lipidomic profiles of individuals with familial and population-ascertained hyperlipidemias.Methods and Results: We determined incident CAD risk for 760 members of 66 hyperlipidemic families (≥ 2 first degree relatives with the same hyperlipidemia) and 19,644 Finnish FINRISK population study participants. We also quantified 151 lipid species in plasma or serum samples from 550 members of 73 hyperlipidemic pedigrees and 897 FINRISK participants using a mass spectrometric shotgun lipidomics platform. Hyperlipidemias (LDL-C or triacylglycerides over 90th population percentile) were associated with increased CAD risk (high LDL-C: HR 1.74, 95% CI 1.48–2.04; high triacylglycerides: HR 1.38, 95% CI 1.09–1.74) and the risk estimates were very similar between the family and population samples. High LDL-C was associated with altered levels of 105 lipid species in families (p-value range 0.033–7.3*10−20 at 5% false discovery rate) and 51 species in the population samples (p-value range 0.017–6.8*10−21). Hypertriglyceridemia was associated with altered levels of 117 lipid species in families (p-value range 0.035–1.8*10−49) and 119 species in the population sample (p-value range 0.038–2.3*10−56). The lipidomics profiles of hyperlipidemias were highly similar in families and population samples.Conclusion: We identified distinct lipidomic profiles associated with high LDL-C and triacylglyceride levels. CAD risk, lipidomic profiles and genetic profiles are highly similar between familial and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms. Our results do not support different screening and treatment for such hyperlipidemias.

Familial hyperlipidemias including but not limited to familial hypercholesterolemia (FH) are often evaluated distinctly from population-based hyperlipidemias. We asked whether this practice is warranted either by greater coronary artery disease (CAD) risk or by different detailed lipid profiles in

Hyperlipidemia, particularly high LDL-C or TG, is the most important heritable risk factor for coronary artery disease (CAD). Its most severe form, monogenic familial hypercholesterolemia (FH) increases CAD risk more than expected from a single LDL-C measurement, likely due to lifelong cumulative

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined., Author Summary Familial combined hyperlipidemia (FCH) is a familial dyslipidemia and the most common familial risk factor for premature coronary heart disease. Its genetic architecture is poorly understood. Rare high-impact variants have been identified in some patients, but have not explained a substantial portion of the trait. FCH has previously been speculated to be a polygenic disorder, but genetic data supporting this hypothesis have so far been incomplete. We provide experimental evidence for the polygenicity and heterogeneity of FCH in a large set of affected families using comprehensive genome-wide variant data. Approximately a third of the affected FCH individuals in our sample had high polygenic burden, and only a minority carried high-impact variants identifiable by genotyping. We show that the polygenic burden of affected FCH family members is comparable to that observed in individuals with similar lipid phenotypes in the general population. Genetic variants identified in large-scale population studies can also underlie the typical phenotypes observed in complex familial diseases such as FCH. Advances in genetic diagnosis based on population samples may thus also benefit FCH families. Families without high polygenic burden are good candidates for sequencing studies to identify rare variants not observable with genotyping.

Background Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk. Methods and Results We derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project. In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95th percentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS). Conclusions The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood.We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content.We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%).We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine.BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance.