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Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

ABSTRACT: Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

SUBMITTER: Goodrich JK

PROVIDER: S-EPMC8190084 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Goodrich Julia K JK Singer-Berk Moriel M Son Rachel R Sveden Abigail A Wood Jordan J England Eleina E Cole Joanne B JB Weisburd Ben B Watts Nick N Caulkins Lizz L Dornbos Peter P Koesterer Ryan R Zappala Zachary Z Zhang Haichen H Maloney Kristin A KA Dahl Andy A Aguilar-Salinas Carlos A CA Atzmon Gil G Barajas-Olmos Francisco F Barzilai Nir N Blangero John J Boerwinkle Eric E Bonnycastle Lori L LL Bottinger Erwin E Bowden Donald W DW Centeno-Cruz Federico F Chambers John C JC Chami Nathalie N Chan Edmund E Chan Juliana J Cheng Ching-Yu CY Cho Yoon Shin YS Contreras-Cubas Cecilia C Córdova Emilio E Correa Adolfo A DeFronzo Ralph A RA Duggirala Ravindranath R Dupuis Josée J Garay-Sevilla Ma Eugenia ME García-Ortiz Humberto H Gieger Christian C Glaser Benjamin B González-Villalpando Clicerio C Gonzalez Ma Elena ME Grarup Niels N Groop Leif L Gross Myron M Haiman Christopher C Han Sohee S Hanis Craig L CL Hansen Torben T Heard-Costa Nancy L NL Henderson Brian E BE Hernandez Juan Manuel Malacara JMM Hwang Mi Yeong MY Islas-Andrade Sergio S Jørgensen Marit E ME Kang Hyun Min HM Kim Bong-Jo BJ Kim Young Jin YJ Koistinen Heikki A HA Kooner Jaspal Singh JS Kuusisto Johanna J Kwak Soo-Heon SH Laakso Markku M Lange Leslie L Lee Jong-Young JY Lee Juyoung J Lehman Donna M DM Linneberg Allan A Liu Jianjun J Loos Ruth J F RJF Lyssenko Valeriya V Ma Ronald C W RCW Martínez-Hernández Angélica A Meigs James B JB Meitinger Thomas T Mendoza-Caamal Elvia E Mohlke Karen L KL Morris Andrew D AD Morrison Alanna C AC Ng Maggie C Y MCY Nilsson Peter M PM O'Donnell Christopher J CJ Orozco Lorena L Palmer Colin N A CNA Park Kyong Soo KS Post Wendy S WS Pedersen Oluf O Preuss Michael M Psaty Bruce M BM Reiner Alexander P AP Revilla-Monsalve Cristina C Rich Stephen S SS Rotter Jerome I JI Saleheen Danish D Schurmann Claudia C Sim Xueling X Sladek Rob R Small Kerrin S KS So Wing Yee WY Spector Timothy D TD Strauch Konstantin K Strom Tim M TM Tai E Shyong ES Tam Claudia H T CHT Teo Yik Ying YY Thameem Farook F Tomlinson Brian B Tracy Russell P RP Tuomi Tiinamaija T Tuomilehto Jaakko J Tusié-Luna Teresa T van Dam Rob M RM Vasan Ramachandran S RS Wilson James G JG Witte Daniel R DR Wong Tien-Yin TY Burtt Noël P NP Zaitlen Noah N McCarthy Mark I MI Boehnke Michael M Pollin Toni I TI Flannick Jason J Mercader Josep M JM O'Donnell-Luria Anne A Baxter Samantha S Florez Jose C JC MacArthur Daniel G DG Udler Miriam S MS

Nature communications 20210609 1

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype a ...[more]

PMID: 34108472

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Project description:BackgroundThere is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features.MethodsUK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative.ResultsAmong 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes.ConclusionsIn the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

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Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Publications

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

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