TY - JOUR
T1 - Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
AU - AMP-T2D-GENES Consortia
AU - Goodrich, Julia K.
AU - Singer-Berk, Moriel
AU - Son, Rachel
AU - Sveden, Abigail
AU - Wood, Jordan
AU - England, Eleina
AU - Cole, Joanne B.
AU - Weisburd, Ben
AU - Watts, Nick
AU - Caulkins, Lizz
AU - Dornbos, Peter
AU - Koesterer, Ryan
AU - Zappala, Zachary
AU - Zhang, Haichen
AU - Maloney, Kristin A.
AU - Dahl, Andy
AU - Aguilar-Salinas, Carlos A.
AU - Atzmon, Gil
AU - Barajas-Olmos, Francisco
AU - Barzilai, Nir
AU - Blangero, John
AU - Boerwinkle, Eric
AU - Bonnycastle, Lori L.
AU - Bottinger, Erwin
AU - Bowden, Donald W.
AU - Centeno-Cruz, Federico
AU - Chambers, John C.
AU - Chami, Nathalie
AU - Chan, Edmund
AU - Chan, Juliana
AU - Cheng, Ching Yu
AU - Cho, Yoon Shin
AU - Contreras-Cubas, Cecilia
AU - Córdova, Emilio
AU - Correa, Adolfo
AU - DeFronzo, Ralph A.
AU - Duggirala, Ravindranath
AU - Dupuis, Josée
AU - Garay-Sevilla, Ma Eugenia
AU - García-Ortiz, Humberto
AU - Gieger, Christian
AU - Glaser, Benjamin
AU - González-Villalpando, Clicerio
AU - Gonzalez, Ma Elena
AU - Grarup, Niels
AU - Groop, Leif
AU - Gross, Myron
AU - Haiman, Christopher
AU - Han, Sohee
AU - Hanis, Craig L.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6/9
Y1 - 2021/6/9
N2 - 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.
AB - 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.
KW - Adult
KW - Biological Variation, Population
KW - Biomarkers/metabolism
KW - Diabetes Mellitus, Type 2/genetics
KW - Dyslipidemias/genetics
KW - Exome/genetics
KW - Genetic Predisposition to Disease/genetics
KW - Genotype
KW - Humans
KW - Multifactorial Inheritance
KW - Penetrance
KW - Risk Assessment
UR - http://www.scopus.com/inward/record.url?scp=85107774343&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-23556-4
DO - 10.1038/s41467-021-23556-4
M3 - Article
C2 - 34108472
AN - SCOPUS:85107774343
SN - 2041-1723
VL - 12
SP - 3505
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3505
ER -