| Title: | Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes |
| Journal: | Nature Communications |
| Published: | 9 Jun 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34108472/ |
| DOI: | https://doi.org/10.1038/s41467-021-23556-4 |
| URL: | https://escholarship.org/uc/item/0dd6m6fw |
| Citations: | 60 (31 in last 2 years) as of 8 Aug 2024 |
Publication 4661
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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.</p>
12 Keywords
- Adult
- Biological Variation, Population
- Biomarkers
- Diabetes Mellitus, Type 2
- Dyslipidemias
- Exome
- Genetic Predisposition to Disease
- Genotype
- Humans
- Multifactorial Inheritance
- Penetrance
- Risk Assessment
130 Authors
- Julia K. Goodrich
- Moriel Singer-Berk
- Rachel Son
- Abigail Sveden
- Jordan Wood
- Eleina England
- Joanne B. Cole
- Ben Weisburd
- Nick Watts
- Lizz Caulkins
- Peter Dornbos
- Ryan Koesterer
- Zachary Zappala
- Haichen Zhang
- Kristin A. Maloney
- Andy Dahl
- Carlos A. Aguilar-Salinas
- Gil Atzmon
- Francisco Barajas-Olmos
- Nir Barzilai
- John Blangero
- Eric Boerwinkle
- Lori L. Bonnycastle
- Erwin Bottinger
- Donald W. Bowden
- Federico Centeno-Cruz
- John C. Chambers
- Nathalie Chami
- Edmund Chan
- Juliana Chan
- Ching-Yu Cheng
- Yoon Shin Cho
- Cecilia Contreras-Cubas
- Emilio Córdova
- Adolfo Correa
- Ralph A. DeFronzo
- Ravindranath Duggirala
- Josée Dupuis
- Ma Eugenia Garay-Sevilla
- Humberto García-Ortiz
- Christian Gieger
- Benjamin Glaser
- Clicerio González-Villalpando
- Ma Elena Gonzalez
- Niels Grarup
- Leif Groop
- Myron Gross
- Christopher Haiman
- Sohee Han
- Craig L. Hanis
- Torben Hansen
- Nancy L. Heard-Costa
- Brian E. Henderson
- Juan Manuel Malacara Hernandez
- Mi Yeong Hwang
- Sergio Islas-Andrade
- Marit E. Jørgensen
- Hyun Min Kang
- Bong-Jo Kim
- Young Jin Kim
- Heikki A. Koistinen
- Jaspal Singh Kooner
- Johanna Kuusisto
- Soo-Heon Kwak
- Markku Laakso
- Leslie Lange
- Jong-Young Lee
- Juyoung Lee
- Donna M. Lehman
- Allan Linneberg
- Jianjun Liu
- Ruth J. F. Loos
- Valeriya Lyssenko
- Ronald C. W. Ma
- Angélica Martínez-Hernández
- James B. Meigs
- Thomas Meitinger
- Elvia Mendoza-Caamal
- Karen L. Mohlke
- Andrew D. Morris
- Alanna C. Morrison
- Maggie C. Y. Ng
- Peter M. Nilsson
- Christopher J. O'Donnell
- Lorena Orozco
- Colin N. A. Palmer
- Kyong Soo Park
- Wendy S. Post
- Oluf Pedersen
- Michael Preuss
- Bruce M. Psaty
- Alexander P. Reiner
- Cristina Revilla-Monsalve
- Stephen S. Rich
- Jerome I. Rotter
- Danish Saleheen
- Claudia Schurmann
- Xueling Sim
- Rob Sladek
- Kerrin S. Small
- Wing Yee So
- Timothy D. Spector
- Konstantin Strauch
- Tim M. Strom
- E. Shyong Tai
- Claudia H. T. Tam
- Yik Ying Teo
- Farook Thameem
- Brian Tomlinson
- Russell P. Tracy
- Tiinamaija Tuomi
- Jaakko Tuomilehto
- Teresa Tusié-Luna
- Rob M. van Dam
- Ramachandran S. Vasan
- James G. Wilson
- Daniel R. Witte
- Tien-Yin Wong
- Noël P. Burtt
- Noah Zaitlen
- Mark I. McCarthy
- Michael Boehnke
- Toni I. Pollin
- Jason Flannick
- Josep M. Mercader
- Anne O'Donnell-Luria
- Samantha Baxter
- Jose C. Florez
- Daniel G. MacArthur
- Miriam S. Udler
Enabling scientific discoveries that improve human health