A Convergent Molecular Network Underlying Autism and Congenital Heart Disease

Overview

Journal Cell Syst

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2021 Aug 19

PMID 34411509

Citations 16

Authors

Sara Brin Rosenthal

Helen Rankin Willsey

Yuxiao Xu

Yuan Mei

Jeanselle Dea

Sheng Wang

Charlotte Curtis

Emily Sempou

Mustafa K Khokha

Neil C Chi

Arthur Jeremy Willsey

Kathleen M Fisch

Trey Ideker

Affiliations

Soon will be listed here.

Abstract

Patients with neurodevelopmental disorders, including autism, have an elevated incidence of congenital heart disease, but the extent to which these conditions share molecular mechanisms remains unknown. Here, we use network genetics to identify a convergent molecular network underlying autism and congenital heart disease. This network is impacted by damaging genetic variants from both disorders in multiple independent cohorts of patients, pinpointing 101 genes with shared genetic risk. Network analysis also implicates risk genes for each disorder separately, including 27 previously unidentified genes for autism and 46 for congenital heart disease. For 7 genes with shared risk, we create engineered disruptions in Xenopus tropicalis, confirming both heart and brain developmental abnormalities. The network includes a family of ion channels, such as the sodium transporter SCN2A, linking these functions to early heart and brain development. This study provides a road map for identifying risk genes and pathways involved in co-morbid conditions.

Citing Articles

Noncoding variants and sulcal patterns in congenital heart disease: Machine learning to predict functional impact.

Mondragon-Estrada E, Newburger J, DePalma S, Brueckner M, Cleveland J, Chung W iScience. 2025; 28(2):111707.

PMID: 39877905 PMC: 11772982. DOI: 10.1016/j.isci.2024.111707.

Mental health in adult congenital heart disease.

Moons P, Van Bulck L, Daelman B, Luyckx K Int J Cardiol Congenit Heart Dis. 2024; 12:100455.

PMID: 39711816 PMC: 11657484. DOI: 10.1016/j.ijcchd.2023.100455.

Convergence of autism proteins at the cilium.

Kostyanovskaya E, Lasser M, Wang B, Schmidt J, Bader E, Buteo C bioRxiv. 2024; .

PMID: 39677731 PMC: 11643032. DOI: 10.1101/2024.12.05.626924.

Trisomy 21 and Congenital Heart Disease: Impact on Health and Functional Outcomes From Birth Through Adolescence: A Scientific Statement From the American Heart Association.

Peterson J, Clarke S, Gelb B, Kasparian N, Kazazian V, Pieciak K J Am Heart Assoc. 2024; 13(19):e036214.

PMID: 39263820 PMC: 11681493. DOI: 10.1161/JAHA.124.036214.

Ciliary biology intersects autism and congenital heart disease.

Teerikorpi N, Lasser M, Wang S, Kostyanovskaya E, Bader E, Sun N bioRxiv. 2024; .

PMID: 39131273 PMC: 11312554. DOI: 10.1101/2024.07.30.602578.

References

Hwang W, Marquez J, Khokha M . : Driving the Discovery of Novel Genes in Patient Disease and Their Underlying Pathological Mechanisms Relevant for Organogenesis. Front Physiol. 2019; 10:953. PMC: 6682594. DOI: 10.3389/fphys.2019.00953. View

Sanders S, Campbell A, Cottrell J, Moller R, Wagner F, Auldridge A . Progress in Understanding and Treating SCN2A-Mediated Disorders. Trends Neurosci. 2018; 41(7):442-456. PMC: 6015533. DOI: 10.1016/j.tins.2018.03.011. View

Morton P, Ishibashi N, Jonas R . Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation. Circ Res. 2017; 120(6):960-977. PMC: 5409515. DOI: 10.1161/CIRCRESAHA.116.309048. View

Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton J . De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013; 498(7453):220-3. PMC: 3706629. DOI: 10.1038/nature12141. View

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

ORoak B, Vives L, Girirajan S, Karakoc E, Krumm N, Coe B . Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012; 485(7397):246-50. PMC: 3350576. DOI: 10.1038/nature10989. View

Willsey H, Exner C, Xu Y, Everitt A, Sun N, Wang B . Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience. Neuron. 2021; 109(5):788-804.e8. PMC: 8132462. DOI: 10.1016/j.neuron.2021.01.002. View

Brinkman E, Chen T, Amendola M, van Steensel B . Easy quantitative assessment of genome editing by sequence trace decomposition. Nucleic Acids Res. 2014; 42(22):e168. PMC: 4267669. DOI: 10.1093/nar/gku936. View

Izarzugaza J, Ellesoe S, Doganli C, Ehlers N, Dalgaard M, Audain E . Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease. Genome Med. 2020; 12(1):76. PMC: 7453558. DOI: 10.1186/s13073-020-00772-z. View

10.

Colbert C, Pan E . Ion channel properties underlying axonal action potential initiation in pyramidal neurons. Nat Neurosci. 2002; 5(6):533-8. DOI: 10.1038/nn0602-857. View

11.

Flint J, Ideker T . The great hairball gambit. PLoS Genet. 2019; 15(11):e1008519. PMC: 6910700. DOI: 10.1371/journal.pgen.1008519. View

12.

Yu M, Ma J, Ono K, Zheng F, Fong S, Gary A . DDOT: A Swiss Army Knife for Investigating Data-Driven Biological Ontologies. Cell Syst. 2019; 8(3):267-273.e3. PMC: 7042149. DOI: 10.1016/j.cels.2019.02.003. View

13.

Fischbach G, Lord C . The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010; 68(2):192-5. DOI: 10.1016/j.neuron.2010.10.006. View

14.

Ackerman M . The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc. 1998; 73(3):250-69. DOI: 10.4065/73.3.250. View

15.

Harris M, Clark J, Ireland A, Lomax J, Ashburner M, Foulger R . The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res. 2003; 32(Database issue):D258-61. PMC: 308770. DOI: 10.1093/nar/gkh036. View

16.

Parikshak N, Luo R, Zhang A, Won H, Lowe J, Chandran V . Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 2013; 155(5):1008-21. PMC: 3934107. DOI: 10.1016/j.cell.2013.10.031. View

17.

Guney E, Menche J, Vidal M, Barabasi A . Network-based in silico drug efficacy screening. Nat Commun. 2016; 7:10331. PMC: 4740350. DOI: 10.1038/ncomms10331. View

18.

Grove J, Ripke S, Als T, Mattheisen M, Walters R, Won H . Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019; 51(3):431-444. PMC: 6454898. DOI: 10.1038/s41588-019-0344-8. View

19.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

20.

Yandim C, Karakulah G . Expression dynamics of repetitive DNA in early human embryonic development. BMC Genomics. 2019; 20(1):439. PMC: 6545021. DOI: 10.1186/s12864-019-5803-1. View