Improving reporting standards for polygenic scores in risk prediction studies.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.

Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

BACKGROUND: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort. METHODS: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data. RESULTS: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia. CONCLUSIONS: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

The clinical utility of polygenic risk scores for combined hyperlipidemia.

PURPOSE OF REVIEW: Combined hyperlipidemia is the most common lipid disorder and is strongly polygenic. Given its prevalence and associated risk for atherosclerotic cardiovascular disease, this review describes the potential for utilizing polygenic risk scores for risk prediction and management of combined hyperlipidemia. RECENT FINDINGS: Different diagnostic criteria have led to inconsistent prevalence estimates and missed diagnoses. Given that individuals with combined hyperlipidemia have risk estimates for incident coronary artery disease similar to individuals with familial hypercholesterolemia, early identification and therapeutic management of those affected is crucial. With diagnostic criteria including traits such apolipoprotein B, low-density lipoprotein cholesterol, and triglyceride, polygenic risk scores for these traits strongly associate with combined hyperlipidemia and could be used in combination for clinical risk prediction models and developing specific treatment plans for patients. SUMMARY: Polygenic risk scores are effective tools in risk prediction of combined hyperlipidemia, can provide insight into disease pathophysiology, and may be useful in managing and guiding treatment plans for patients. However, efforts to ensure equitable polygenic risk score performance across different genetic ancestry groups is necessary before clinical implementation in order to prevent the exacerbation of racial disparities in the clinic.

The impact of receiving polygenic risk scores for alcohol use disorder on psychological distress, risk perception, and intentions to reduce drinking.

For the return of polygenic risk scores to become an acceptable clinical practice in psychiatry, receipt of polygenic risk scores must be associated with minimal harm and changes in behavior that decrease one's risk for developing a psychiatric outcome. Data from a randomized controlled trial was used to assess the impact of different levels of hypothetical polygenic risk scores for alcohol use disorder on psychological distress, risk perception, and intentions to change drinking behaviors. The analytic sample consisted of 325 participants recruited from an urban, public university. Results demonstrated that there were significant increases in psychological distress as the level of genetic risk for alcohol use disorder increased. In addition, the perceived chance of developing alcohol use disorder significantly increased as the level of genetic risk increased. Promisingly, a greater proportion of participants indicated that they would intend to engage in follow-up behaviors, such as seeking additional information, talking to a healthcare provider about risk, and reducing drinking behaviors, as the level of genetic risk increased. Returning polygenic risk scores for alcohol use disorder in a clinical setting has the potential to promote risk-reducing behavior change, especially with increasing levels of genetic risk. The study was registered on ClinicalTrials.gov (Identifier: NCT05143073).

Human variant of scavenger receptor BI (R174C) exhibits impaired cholesterol transport functions.

HDL and its primary receptor, scavenger receptor class B type I (SR-BI), work together to promote the clearance of excess plasma cholesterol, thereby protecting against atherosclerosis. Human variants of SR-BI have been identified in patients with high HDL-cholesterol levels, and at least one variant has been linked to cardiovascular disease. Therefore, while often regarded as beneficial, very high levels of HDL-cholesterol may result from impaired cholesterol clearance through SR-BI and contribute to cardiovascular risk. In this study, we characterized the function of a rare human variant of SR-BI, resulting in the substitution of arginine-174 with cysteine (R174C), which was previously identified in a heterozygous individual with high levels of HDL-cholesterol. We hypothesized that the R174C-SR-BI variant has impaired cholesterol transport functions, which were assessed in COS-7 cells after transient transfection with full-length WT or R174C-SR-BI. Although R174C-SR-BI was expressed at levels comparable to the WT receptor, HDL binding, cholesteryl hexadecyl ether uptake, free cholesterol efflux, and modulation of membrane cholesterol were disrupted in the presence of R174C-SR-BI. We further examined the role of salt bridges as a potential mechanism for R174C-SR-BI dysfunction. If translatable, this human variant could lead to increased plasma HDL-cholesterol levels, impaired cholesterol clearance, and increased cardiovascular disease risk.

Genetics of hypertriglyceridemia and atherosclerosis.

PURPOSE OF REVIEW: The relationship between elevated triglyceride levels (i.e. hypertriglyceridemia) and risk of atherosclerotic cardiovascular disease (ASCVD) has been investigated for decades. Recent genetic studies have sought to resolve the decades-old question of a causal relationship. RECENT FINDINGS: Genetic studies seem to demonstrate associations between elevated triglyceride levels and ASCVD risk. Mendelian randomization studies suggest this association may be causal. However, simultaneous pleiotropic effects of metabolically linked lipid variables - such as non-HDL cholesterol, apolipoprotein B and HDL cholesterol -- often go unaccounted for in these studies. Complex underlying pleiotropic interactions of triglycerides with these lipid fractions together with unmeasured intercalated nonlipid-related mechanisms, such as inflammation and coagulation, impair the ability of genetic studies to implicate a direct role for triglycerides on ASCVD risk. One potential mechanism seems largely driven by the cholesterol carried within triglyceride-rich lipoproteins and their remnants, rather than their triglyceride content. SUMMARY: Although the exact mechanisms linking elevated triglyceride levels to ASCVD remain to be determined, new therapeutics that reduce triglyceride levels might be advantageous in certain patients. Newer investigational triglyceride-lowering therapies derived from human genetics target key proteins, such as apo C-III and ANGPTL3. Although these treatments clearly lower triglyceride levels, their efficacy in atherosclerotic risk reduction remains unproven.

2019 George Lyman Duff Memorial Lecture: Three Decades of Examining DNA in Patients With Dyslipidemia.

Dyslipidemias include both rare single gene disorders and common conditions that have a complex underlying basis. In London, ON, there is fortuitous close physical proximity between the Lipid Genetics Clinic and the London Regional Genomics Centre. For >30 years, we have applied DNA sequencing of clinical samples to help answer scientific questions. More than 2000 patients referred with dyslipidemias have participated in an ongoing translational research program. In 2013, we transitioned to next-generation sequencing; our targeted panel is designed to concurrently assess both monogenic and polygenic contributions to dyslipidemias. Patient DNA is screened for rare variants underlying 25 mendelian dyslipidemias, including familial hypercholesterolemia, hepatic lipase deficiency, abetalipoproteinemia, and familial chylomicronemia syndrome. Furthermore, polygenic scores for LDL (low-density lipoprotein) and HDL (high-density lipoprotein) cholesterol, and triglycerides are calculated for each patient. We thus simultaneously document both rare and common genetic variants, allowing for a broad view of genetic predisposition for both individual patients and cohorts. For instance, among patients referred with severe hypertriglyceridemia, defined as ≥10 mmol/L (≥885 mg/dL), <1% have a mendelian disorder (ie, autosomal recessive familial chylomicronemia syndrome), ≈15% have heterozygous rare variants (a >3-fold increase over normolipidemic individuals), and ≈35% have an extreme polygenic score (a >3-fold increase over normolipidemic individuals). Other dyslipidemias show a different mix of genetic determinants. Genetic results are discussed with patients and can support clinical decision-making. Integrating DNA testing into clinical care allows for a bidirectional flow of information, which facilitates scientific discoveries and clinical translation.

Loss-of-Function CREB3L3 Variants in Patients With Severe Hypertriglyceridemia.

OBJECTIVE: Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11-366.1; P=0.03) more likely than controls to carry a rare loss-of-function variant in CREB3L3, which encodes a transcription factor that regulates several target genes with roles in triglyceride metabolism. CONCLUSIONS: Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely CREB3L3, contribute significantly to severe hypertriglyceridemia. Secondary genes and pathways should be considered when evaluating the genetic architecture of this complex trait.

Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in 'lone' atrial fibrillation.

AIMS: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF. METHODS AND RESULTS: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF. CONCLUSION: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.

PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

The evolution of genetic-based risk scores for lipids and cardiovascular disease.

PURPOSE OF REVIEW: With improved next-generation sequencing technology, open-access genetic databases and increased awareness of complex trait genetics, we are entering a new era of risk assessment in which genetic-based risk scores (GRSs) will play a clinical role. We review the concepts underlying polygenic models of disease susceptibility and challenges in clinical implementation. RECENT FINDINGS: Polygenic risk scores are currently used in genetic research on dyslipidemias and cardiovascular disease (CVD). Although the underlying principles for constructing polygenic scores for lipids are established, the lack of consensus on which score to use is indicated by the large number - about 50 - that have been published. Recently, large-scale polygenic scores for CVD appear to afford superior risk prediction compared to small-scale scores. Despite the potential benefits of GRSs, certain biases towards ethnicity and sex need to be worked through. SUMMARY: We are on the verge of clinical application of GRSs to provide incremental information on dyslipidemia and CVD risk above and beyond traditional clinical variables. Additional work is required to develop a consensus of how such scores will be constructed and measured in a validated manner, as well as clinical indications for their use.

Progress in finding pathogenic DNA copy number variations in dyslipidemia.

PURPOSE OF REVIEW: DNA copy number variations (CNVs) are large-scale mutations that include deletions and duplications larger than 50 bp in size. In the era when single-nucleotide variations were the major focus of genetic technology and research, CNVs were largely overlooked. However, CNVs clearly underlie a substantial proportion of clinical disorders. Here, we update recent progress in identifying CNVs in dyslipidemias. RECENT FINDINGS: Until last year, only the LDLR and LPA genes were appreciated as loci within which clinically relevant CNVs contributed to familial hypercholesterolemia and variation in Lp(a) levels, respectively. Since 2017, next-generation sequencing panels have identified pathogenic CNVs in at least five more genes underlying dyslipidemias, including a PCSK9 whole-gene duplication in familial hypercholesterolemia; LPL, GPIHBP1, and APOC2 deletions in hypertriglyceridemia; and ABCA1 deletions in hypoalphalipoproteinemia. SUMMARY: CNVs are an important class of mutation that contribute to the molecular genetic heterogeneity underlying dyslipidemias. Clinical applications of next-generation sequencing technologies need to consider CNVs concurrently with familiar small-scale genetic variation, given the likely implications for improved diagnosis and treatment.

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

Targeted sequencing reveals expanded genetic diversity of human transfer RNAs.

Transfer RNAs are required to translate genetic information into proteins as well as regulate other cellular processes. Nucleotide changes in tRNAs can result in loss or gain of function that impact the composition and fidelity of the proteome. Despite links between tRNA variation and disease, the importance of cytoplasmic tRNA variation has been overlooked. Using a custom capture panel, we sequenced 605 human tRNA-encoding genes from 84 individuals. We developed a bioinformatic pipeline that allows more accurate tRNA read mapping and identifies multiple polymorphisms occurring within the same variant. Our analysis identified 522 unique tRNA-encoding sequences that differed from the reference genome from 84 individuals. Each individual had ~66 tRNA variants including nine variants found in less than 5% of our sample group. Variants were identified throughout the tRNA structure with 17% predicted to enhance function. Eighteen anticodon mutants were identified including potentially mistranslating tRNAs; e.g., a tRNASer that decodes Phe codons. Similar engineered tRNA variants were previously shown to inhibit cell growth, increase apoptosis and induce the unfolded protein response in mammalian cell cultures and chick embryos. Our analysis shows that human tRNA variation has been underestimated. We conclude that the large number of tRNA genes provides a buffer enabling the emergence of variants, some of which could contribute to disease.

Polygenic influences on dyslipidemias.

PURPOSE OF REVIEW: Rare large-effect genetic variants underlie monogenic dyslipidemias, whereas common small-effect genetic variants - single nucleotide polymorphisms (SNPs) - have modest influences on lipid traits. Over the past decade, these small-effect SNPs have been shown to cumulatively exert consistent effects on lipid phenotypes under a polygenic framework, which is the focus of this review. RECENT FINDINGS: Several groups have reported polygenic risk scores assembled from lipid-associated SNPs, and have applied them to their respective phenotypes. For lipid traits in the normal population distribution, polygenic effects quantified by a score that integrates several common polymorphisms account for about 20-30% of genetic variation. Among individuals at the extremes of the distribution, that is, those with clinical dyslipidemia, the polygenic component includes both rare variants with large effects and common polymorphisms: depending on the trait, 20-50% of susceptibility can be accounted for by this assortment of genetic variants. SUMMARY: Accounting for polygenic effects increases the numbers of dyslipidemic individuals who can be explained genetically, but a substantial proportion of susceptibility remains unexplained. Whether documenting the polygenic basis of dyslipidemia will affect outcomes in clinical trials or prospective observational studies remains to be determined.

Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia.

Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.

Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants.

PURPOSE OF REVIEW: There are many reports of human variants in proprotein convertase subtilisin-kexin type 9 (PCSK9) that are either gain-of-function (GOF) or loss-of-function (LOF), with downstream effects on LDL cholesterol and cardiovascular disease (CVD) risk. However, data on particular mechanisms have only been minimally curated. RECENT FINDINGS: GOF variants are individually ultrarare, affect all domains of the protein, act to reduce LDL receptor expression through several mechanisms, are a minor cause of familial hypercholesterolemia, have been reported mainly within families, have variable LDL cholesterol-raising effects, and are associated with increased CVD risk mainly through observational studies in families and small cohorts. In contrast, LOF variants can be either ultrarare mutations or relatively more common polymorphisms seen in populations, affect all domains of the protein, act to increase LDL receptor expression through several mechanisms, have variable LDL cholesterol-lowering effects, and have been associated with decreased CVD risk mainly through Mendelian randomization studies in epidemiologic populations. SUMMARY: There is considerable complexity underlying the clinical concept of both LOF and GOF variants of PCSK9. But despite the underlying mechanistic heterogeneity, altered PCSK9 secretion or function is ultimately correlated with plasma LDL cholesterol level, which is also the driver of CVD outcomes.

Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a heritable condition of severely elevated LDL cholesterol, caused predominantly by autosomal codominant mutations in the LDL receptor gene (LDLR). In providing a molecular diagnosis for FH, the current procedure often includes targeted next-generation sequencing (NGS) panels for the detection of small-scale DNA variants, followed by multiplex ligation-dependent probe amplification (MLPA) in LDLR for the detection of whole-exon copy number variants (CNVs). The latter is essential because ∼10% of FH cases are attributed to CNVs in LDLR; accounting for them decreases false negative findings. Here, we determined the potential of replacing MLPA with bioinformatic analysis applied to NGS data, which uses depth-of-coverage analysis as its principal method to identify whole-exon CNV events. In analysis of 388 FH patient samples, there was 100% concordance in LDLR CNV detection between these two methods: 38 reported CNVs identified by MLPA were also successfully detected by our NGS method, while 350 samples negative for CNVs by MLPA were also negative by NGS. This result suggests that MLPA can be removed from the routine diagnostic screening for FH, significantly reducing associated costs, resources, and analysis time, while promoting more widespread assessment of this important class of mutations across diagnostic laboratories.

Polygenic determinants in extremes of high-density lipoprotein cholesterol.

HDL cholesterol (HDL-C) remains a superior biochemical predictor of CVD risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery cohort of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation and included 1,746 individuals from the Montréal Heart Institute Biobank and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low- and high-HDL-C patients, respectively. We also found common variant accumulation, indicated by extreme polygenic trait scores, in an additional 12.8% and 19.3% of overall cases of low- and high-HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia.