M-DATA: A statistical approach to jointly analyzing de novo mutations for multiple traits.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Data Interpretation, Statistical* ; Mutation*; Autistic Disorder/*genetics ; Heart Defects, Congenital/*genetics; Algorithms ; Genetic Predisposition to Disease ; Humans

Competing Interests: The authors have declared that no competing interests exist.
Recent studies have demonstrated that multiple early-onset diseases have shared risk genes, based on findings from de novo mutations (DNMs). Therefore, we may leverage information from one trait to improve statistical power to identify genes for another trait. However, there are few methods that can jointly analyze DNMs from multiple traits. In this study, we develop a framework called M-DATA (Multi-trait framework for De novo mutation Association Test with Annotations) to increase the statistical power of association analysis by integrating data from multiple correlated traits and their functional annotations. Using the number of DNMs from multiple diseases, we develop a method based on an Expectation-Maximization algorithm to both infer the degree of association between two diseases as well as to estimate the gene association probability for each disease. We apply our method to a case study of jointly analyzing data from congenital heart disease (CHD) and autism. Our method was able to identify 23 genes for CHD from joint analysis, including 12 novel genes, which is substantially more than single-trait analysis, leading to novel insights into CHD disease etiology.

BioData Min. 2017 Jan 26;10:2. (PMID: 28149325)
Nat Genet. 2019 Jan;51(1):106-116. (PMID: 30559488)
J Hum Genet. 2014 Jan;59(1):5-15. (PMID: 24196381)
Epigenetics Chromatin. 2019 Apr 02;12(1):20. (PMID: 30940185)
Nat Commun. 2019 Oct 17;10(1):4722. (PMID: 31624253)
PLoS Genet. 2013 Jun;9(6):e1003491. (PMID: 23785294)
PLoS Genet. 2013 May;9(5):e1003486. (PMID: 23671422)
Hum Genet. 2014 May;133(5):639-50. (PMID: 24337655)
Curr Protoc Hum Genet. 2013 Jan;Chapter 7:Unit7.20. (PMID: 23315928)
Genome Med. 2016 Jan 06;8(1):3. (PMID: 26739615)
Nat Genet. 2020 Aug;52(8):769-777. (PMID: 32601476)
Am J Hum Genet. 2015 Feb 5;96(2):283-94. (PMID: 25640677)
Nat Genet. 2014 Sep;46(9):944-50. (PMID: 25086666)
Nucleic Acids Res. 2014 Dec 16;42(22):13534-44. (PMID: 25416802)
Nat Protoc. 2015 Oct;10(10):1556-66. (PMID: 26379229)
Genome Biol. 2014 Feb 04;15(2):R32. (PMID: 24495580)
Nat Commun. 2020 Jun 10;11(1):2929. (PMID: 32522981)
Nature. 2020 May;581(7809):434-443. (PMID: 32461654)
PLoS Genet. 2014 Nov 13;10(11):e1004787. (PMID: 25393678)
Am J Hum Genet. 2016 Mar 3;98(3):541-552. (PMID: 26942287)
PLoS Genet. 2014 May 15;10(5):e1004383. (PMID: 24830394)
Bioinformatics. 2018 Aug 15;34(16):2724-2731. (PMID: 29590295)
Nat Genet. 2016 Sep;48(9):1060-5. (PMID: 27479907)
Circulation. 2018 Nov 20;138(21):e653-e711. (PMID: 30571578)
Nat Genet. 2017 Nov;49(11):1593-1601. (PMID: 28991257)
Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2560-2569. (PMID: 31964835)
Am J Hum Genet. 2018 Jun 7;102(6):1031-1047. (PMID: 29754769)
Nat Rev Genet. 2013 Jul;14(7):483-95. (PMID: 23752797)
Nucleic Acids Res. 2017 Jan 4;45(D1):D804-D811. (PMID: 27907889)
PLoS Genet. 2013;9(8):e1003671. (PMID: 23966865)
Nat Commun. 2016 Sep 27;7:12824. (PMID: 27670201)
Brief Bioinform. 2021 Sep 2;22(5):. (PMID: 33791774)
Bioinformatics. 2017 Feb 15;33(4):500-507. (PMID: 28011772)
Quant Biol. 2021 Jun;9(2):216-227. (PMID: 35414959)
Hum Mol Genet. 2010 Oct 15;19(R2):R145-51. (PMID: 20705737)
Science. 2015 Jan 9;347(6218):1254806. (PMID: 25525159)
Nat Commun. 2020 Feb 26;11(1):859. (PMID: 32103003)
PLoS Genet. 2013 Apr;9(4):e1003461. (PMID: 23637629)
Nature. 2013 Jun 13;498(7453):220-3. (PMID: 23665959)
Am J Hum Genet. 2016 Oct 6;99(4):877-885. (PMID: 27666373)
PLoS Genet. 2011 Feb;7(2):e1002004. (PMID: 21383967)
Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276)
Am J Hum Genet. 2018 May 3;102(5):985-994. (PMID: 29656860)
Cell. 2018 Jul 26;174(3):505-520. (PMID: 30053424)
Sci Rep. 2016 Aug 03;6:30896. (PMID: 27485310)
Hum Mutat. 2018 Dec;39(12):1875-1884. (PMID: 30157302)
Circ Res. 2017 Mar 17;120(6):923-940. (PMID: 28302740)
Genome Med. 2017 Dec 20;9(1):114. (PMID: 29262854)
Mol Psychiatry. 2016 Feb;21(2):290-7. (PMID: 25849321)
BMC Bioinformatics. 2018 Mar 9;19(1):95. (PMID: 29523079)
Bioinformatics. 2017 Jul 15;33(14):i67-i74. (PMID: 28881962)
PLoS Genet. 2017 Jun 9;13(6):e1006836. (PMID: 28598966)
Bioinformatics. 2016 Feb 15;32(4):542-8. (PMID: 26504140)
Science. 2015 Dec 4;350(6265):1262-6. (PMID: 26785492)

R01 GM134005 United States GM NIGMS NIH HHS; R03 HD100883 United States HD NICHD NIH HHS

Date Created: 20211104 Date Completed: 20211203 Latest Revision: 20240404

20250114

PMC8568192

10.1371/journal.pgen.1009849

34735430