Prioritized High-Confidence Risk Genes for Intellectual Disability Reveal Molecular Convergence During Brain Development

Overview

Journal Front Genet

Date 2018 Oct 4

PMID 30279698

Citations 10

Authors

Zhenwei Liu

Na Zhang

Yu Zhang

Yaoqiang Du

Tao Zhang

Zhongshan Li

Jinyu Wu

Xiaobing Wang

Affiliations

Soon will be listed here.

Abstract

Dissecting the genetic susceptibility to intellectual disability (ID) based on mutations (DNMs) will aid our understanding of the neurobiological and genetic basis of ID. In this study, we identify 63 high-confidence ID genes with -values < 0.1 based on four background DNM rates and coding DNM data sets from multiple sequencing cohorts. Bioinformatic annotations revealed a higher burden of these 63 ID genes in FMRP targets and CHD8 targets, and these genes show evolutionary constraint against functional genetic variation. Moreover, these ID risk genes were preferentially expressed in the cortical regions from the early fetal to late mid-fetal stages. In particular, a genome-wide weighted co-expression network analysis suggested that ID genes tightly converge onto two biological modules (M1 and M2) during human brain development. Functional annotations showed specific enrichment of chromatin modification and transcriptional regulation for M1 and synaptic function for M2, implying the divergent etiology of the two modules. In addition, we curated 12 additional strong ID risk genes whose molecular interconnectivity with known ID genes (-values < 0.3) was greater than random. These findings further highlight the biological convergence of ID risk genes and help improve our understanding of the genetic architecture of ID.

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References

Petrovski S, Wang Q, Heinzen E, Allen A, Goldstein D . Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013; 9(8):e1003709. PMC: 3749936. DOI: 10.1371/journal.pgen.1003709. View

Nagalski A, Irimia M, Szewczyk L, Ferran J, Misztal K, Kuznicki J . Postnatal isoform switch and protein localization of LEF1 and TCF7L2 transcription factors in cortical, thalamic, and mesencephalic regions of the adult mouse brain. Brain Struct Funct. 2012; 218(6):1531-49. PMC: 3825142. DOI: 10.1007/s00429-012-0474-6. View

Yuen R, Merico D, Cao H, Pellecchia G, Alipanahi B, Thiruvahindrapuram B . Genome-wide characteristics of mutations in autism. NPJ Genom Med. 2016; 1:160271-1602710. PMC: 4980121. DOI: 10.1038/npjgenmed.2016.27. View

Harripaul R, Noor A, Ayub M, Vincent J . The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability. Cold Spring Harb Perspect Med. 2017; 7(3). PMC: 5334248. DOI: 10.1101/cshperspect.a026864. View

Gripp K, Aldinger K, Bennett J, Baker L, Tusi J, Powell-Hamilton N . A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. Am J Med Genet A. 2016; 170(9):2237-47. PMC: 5134331. DOI: 10.1002/ajmg.a.37781. View

Raybaud C . The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation. Neuroradiology. 2010; 52(6):447-77. DOI: 10.1007/s00234-010-0696-3. View

Gilissen C, Hehir-Kwa J, Tjwan Thung D, van de Vorst M, van Bon B, Willemsen M . Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014; 511(7509):344-7. DOI: 10.1038/nature13394. View

Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F . Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules. Am J Hum Genet. 2016; 98(1):149-64. PMC: 4716705. DOI: 10.1016/j.ajhg.2015.11.024. View

. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017; 542(7642):433-438. PMC: 6016744. DOI: 10.1038/nature21062. View

10.

Spencer M, Gibson R, Moorhead T, Keston P, Hoare P, Best J . Qualitative assessment of brain anomalies in adolescents with mental retardation. AJNR Am J Neuroradiol. 2005; 26(10):2691-7. PMC: 7976197. View

11.

Sanders S, Murtha M, Gupta A, Murdoch J, Raubeson M, Willsey A . De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012; 485(7397):237-41. PMC: 3667984. DOI: 10.1038/nature10945. View

12.

Cotney J, Muhle R, Sanders S, Liu L, Willsey A, Niu W . The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun. 2015; 6:6404. PMC: 4355952. DOI: 10.1038/ncomms7404. View

13.

Wolff J, Gerig G, Lewis J, Soda T, Styner M, Vachet C . Altered corpus callosum morphology associated with autism over the first 2 years of life. Brain. 2015; 138(Pt 7):2046-58. PMC: 4492413. DOI: 10.1093/brain/awv118. View

14.

Choi J, Shooshtari P, Samocha K, Daly M, Cotsapas C . Network Analysis of Genome-Wide Selective Constraint Reveals a Gene Network Active in Early Fetal Brain Intolerant of Mutation. PLoS Genet. 2016; 12(6):e1006121. PMC: 4909280. DOI: 10.1371/journal.pgen.1006121. View

15.

Whitford T, Kubicki M, Schneiderman J, ODonnell L, King R, Alvarado J . Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia. Biol Psychiatry. 2010; 68(1):70-7. PMC: 2900500. DOI: 10.1016/j.biopsych.2010.03.025. View

16.

Luo X, Rosenfeld J, Yamamoto S, Harel T, Zuo Z, Hall M . Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. PLoS Genet. 2017; 13(7):e1006905. PMC: 5557584. DOI: 10.1371/journal.pgen.1006905. View

17.

Schatz J, Buzan R . Decreased corpus callosum size in sickle cell disease: relationship with cerebral infarcts and cognitive functioning. J Int Neuropsychol Soc. 2006; 12(1):24-33. DOI: 10.1017/S1355617706060085. View

18.

Maulik P, Mascarenhas M, Mathers C, Dua T, Saxena S . Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil. 2011; 32(2):419-36. DOI: 10.1016/j.ridd.2010.12.018. View

19.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

20.

Shannon P, Markiel A, Ozier O, Baliga N, Wang J, Ramage D . Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-504. PMC: 403769. DOI: 10.1101/gr.1239303. View