Positive predictive value highlights four novel candidates for actionable genetic screening from analysis of 220,000 clinicogenomic records

Barrett, Kelly M Schiabor; Bolze, Alexandre; Ni, Yunyun; White, Simon; Isaksson, Magnus; Sharma, Lavania; Levin, Elissa; Lee, William; Grzymski, Joseph J.; Lu, James T.; Washington, Nicole; Cirulli, Elizabeth T.

doi:10.1038/s41436-021-01293-9

Cited by 15 publications

(22 citation statements)

References 39 publications

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“…The availability of exome sequencing data in nearly 200,000 individuals from the UK Biobank has provided an unparalleled opportunity to explore the genetic basis of common diseases using many distinct analytic approaches 53 - 55 . Through exome-wide gene-based analysis of very rare genetic variants, we replicate many known Mendelian gene-trait associations for cardiometabolic disorders in the UK Biobank.…”

Section: Discussionmentioning

confidence: 99%

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

et al. 2022

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Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3 , LDLR , GCK , PKD1 and TTN . Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large-effect associations for height, and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0 and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.

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Section: Discussionmentioning

confidence: 99%

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

et al. 2022

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“…Our previous work examined rare LoF variants in TTN (equivalent to and hereafter TTN tvs ) with a gene-based collapsing approach in two population-based cohorts (∼25k individuals from the Healthy Nevada Project (HNP) and ∼200K from the UKB). Through these analyses we identified genome-wide significant associations with seven heart phenotypes (“phecodes”, see methods): primary/intrinsic cardiomyopathies (CM), heart failure not otherwise specified (NOS), atrial fibrillation and flutter (Afib), congestive heart failure (CHF) NOS, nonrheumatic mitral valve disorders, mitral valve disease, and tachycardia NOS(24). While DCM and Afib are the most well-described population-level associations, TTN tvs have been implicated in a spectrum of heart disease and subclinical functional measures, including each of the phenotypes identified in these analyses (13,14,25–27).…”

Section: Resultsmentioning

confidence: 99%

“…Plotted is the odds ratio (OR) and positive predictive value (PPV) for the 7 phenotypes identified as significantly associated with TTN tvs in our prior studies (24). The values shown and corresponding p-values are updated based on analysis of the 450k UKB exomes.…”

Section: Resultsmentioning

confidence: 99%

“…We used regenie for genetic analyses as previously described (16,23,24). Our analysis in regenie builds a whole genome regression model using common variants to account for the effects of relatedness and population stratification, and it accounts for situations where there is an extreme case-control imbalance, which can lead to test statistic inflation with other analysis methods.…”

Section: Methodsmentioning

confidence: 99%

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TTN truncating variants in hiPSI exons show high penetrance for cardiomyopathy in carriers with atrial fibrillation

Barrett

Cirulli

Bolze

et al. 2022

Preprint

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Background: Truncating variants in TTN (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCM). At the population level, even when limited to TTNtvs in cardiac-specific exons (hiPSI TTNtvs) penetrance estimates for DCM are low. Recent work shows that individuals harboring TTNtvs have a high prevalence of other cardiac conditions aside from heart failure, in particular, atrial fibrillation (Afib). Objectives: Pinpoint the genetic footprint TTN-related diagnoses aside from DCM, such as Afib, and determine if vetting additional significantly-associated phenotypes better stratifies cardiomyopathy risk across TTN carriers. Methods: We leverage longitudinal EHR and exome sequencing data from two cohorts to determine the penetrance of TTNtvs using multiple gene expression models against Afib, CM, and other cardiac diagnoses. Results: Controlling for CM and Afib, related cardio phenotypes retain only nominal association with TTNtvs. An unbiased sliding window analysis of TTNtvs across the locus confirms the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in lowPSI exons nor improvements from LOFTEE designations. We find 34% of hiPSI TTNtv carriers with early Afib have a CM diagnosis - a 5-fold increase in risk over non-carriers with early Afib and 47-fold increase over population controls. Conclusion: CM and Afib are often coincident in hiPSI TTNtv carriers, which represent varying and progressive manifestations of structurally-based heart failure. We provide statistical support for a hiPSI variant interpretation model for TTNtvs and evidence for the first population-level screening method with clinical utility for cardiomyopathies, especially in relation to an Afib finding.

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“…Patients have mild and stable fasting hyperglycemia within 6-8 mM that does not usually require treatment, in contrast to other types of diabetes. Due to the population prevalence and as GCK-MODY is actionable, it has been proposed that GCK is suitable for inclusion in population screening programs (Schiabor Barrett et al, 2021). To act on variants detected in suspected GCK-MODY patients or in potential future population screening of GCK, we need to know the impact of any given variant on GCK function and its relation to diabetes risk.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive map of human glucokinase variant activity

Gersing

Cagiada

Gebbia

et al. 2022

Preprint

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Diabetes is a complex disease spanning from the heterogeneous etiology of type 1 and type 2 diabetes to monogenic diabetes. A common monogenic form of diabetes is glucokinase (GCK) maturity-onset diabetes of the young (GCK-MODY), which is caused by heterozygous inactivating variants in the gene encoding GCK. GCK is known as the pancreatic glucose sensor, as it regulates insulin secretion to maintain appropriate blood glucose levels. Accordingly, variants that alter GCK activity can cause hypo- and hyperglycemia, associated with hyperinsulinemic hypoglycemia (HH) and GCK-MODY, respectively, affecting up to 10 million people worldwide. Patients with GCK-MODY, in contrast to other people with diabetes, often do not require treatment but are frequently misdiagnosed and treated unnecessarily. Genetic testing can prevent this but is hampered by the challenge of interpreting novel missense variants. To address this, we generated a comprehensive map of GCK variant activity in yeast. The activity map includes 97% of the possible missense and nonsense variants and correlates with in vitro catalytic efficiency, fasting glucose levels in carriers of GCK variants and evolutionary conservation analysis. Activity scores include both hyper- and hypoactive variants. We found that some hyperactive variants shift the conformational equilibrium towards the active state through a relative destabilization of the inactive conformation. As expected, hypoactive variants were concentrated at buried positions, near the active site, and at a partially surface-exposed region involved in GCK conformational dynamics. In conclusion, we provide a comprehensive assessment of GCK variant activity to facilitate variant interpretation and diagnosis, and we expand the mechanistic understanding of hyperactive variants to support development and refinement of drugs targeting GCK.

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Positive predictive value highlights four novel candidates for actionable genetic screening from analysis of 220,000 clinicogenomic records

Cited by 15 publications

References 39 publications

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

TTN truncating variants in hiPSI exons show high penetrance for cardiomyopathy in carriers with atrial fibrillation

A comprehensive map of human glucokinase variant activity

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