Massively Parallel Reporter Assays: Defining Functional Psychiatric Genetic Variants Across Biological Contexts.

Publisher: Elsevier Country of Publication: United States NLM ID: 0213264 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2402 (Electronic) Linking ISSN: 00063223 NLM ISO Abbreviation: Biol Psychiatry Subsets: MEDLINE

Publication: New York, NY : Elsevier
Original Publication: New York, Plenum Pub. Corp.

Clustered Regularly Interspaced Short Palindromic Repeats* ; Genomics*; Genome

Neuropsychiatric phenotypes have long been known to be influenced by heritable risk factors, directly confirmed by the past decade of genetic studies that have revealed specific genetic variants enriched in disease cohorts. However, the initial hope that a small set of genes would be responsible for a given disorder proved false. The more complex reality is that a given disorder may be influenced by myriad small-effect noncoding variants and/or by rare but severe coding variants, many de novo. Noncoding genomic sequences-for which molecular functions cannot usually be inferred-harbor a large portion of these variants, creating a substantial barrier to understanding higher-order molecular and biological systems of disease. Fortunately, novel genetic technologies-scalable oligonucleotide synthesis, RNA sequencing, and CRISPR (clustered regularly interspaced short palindromic repeats)-have opened novel avenues to experimentally identify biologically significant variants en masse. Massively parallel reporter assays (MPRAs) are an especially versatile technique resulting from such innovations. MPRAs are powerful molecular genetics tools that can be used to screen thousands of untranscribed or untranslated sequences and their variants for functional effects in a single experiment. This approach, though underutilized in psychiatric genetics, has several useful features for the field. We review methods for assaying putatively functional genetic variants and regions, emphasizing MPRAs and the opportunities they hold for dissection of psychiatric polygenicity. We discuss literature applying functional assays in neurogenetics, highlighting strengths, caveats, and design considerations-especially regarding disease-relevant variables (cell type, neurodevelopment, and sex), and we ultimately propose applications of MPRA to both computational and experimental neurogenetics of polygenic disease risk.
(Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Nat Commun. 2021 Mar 12;12(1):1611. (PMID: 33712590)
BMC Genomics. 2019 Mar 12;20(1):209. (PMID: 30866806)
Front Genet. 2015 Oct 07;6:301. (PMID: 26500678)
Nucleic Acids Res. 2020 May 7;48(8):4195-4213. (PMID: 32133495)
Science. 2018 Dec 14;362(6420):. (PMID: 30545852)
Genome Biol. 2020 Jan 22;21(1):17. (PMID: 31969180)
Mol Autism. 2015 Mar 11;6:16. (PMID: 25789151)
Nature. 2014 Mar 27;507(7493):462-70. (PMID: 24670764)
Curr Biol. 2013 Apr 8;23(7):R259-61. (PMID: 23578867)
Cell. 2016 Jun 2;165(6):1530-1545. (PMID: 27259154)
Cell Rep. 2024 Feb 27;43(2):113693. (PMID: 38271204)
Nat Genet. 2016 Mar;48(3):245-52. (PMID: 26854917)
PLoS Genet. 2012;8(11):e1003067. (PMID: 23209433)
Neuron. 2021 May 5;109(9):1449-1464.e13. (PMID: 33789083)
Nat Genet. 2014 Aug;46(8):881-5. (PMID: 25038753)
Nature. 2018 Feb 8;554(7691):239-243. (PMID: 29420474)
Nature. 2019 Sep;573(7772):61-68. (PMID: 31435019)
Nat Commun. 2016 Oct 05;7:12923. (PMID: 27703156)
Nat Commun. 2018 May 8;9(1):1825. (PMID: 29739930)
Nat Commun. 2018 Jan 19;9(1):301. (PMID: 29352242)
Am J Med Genet B Neuropsychiatr Genet. 2020 Jan;183(1):61-73. (PMID: 31503409)
Nat Genet. 2013 Sep;45(9):984-94. (PMID: 23933821)
Cell. 2019 Oct 17;179(3):750-771.e22. (PMID: 31626773)
Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):E180-E189. (PMID: 29269392)
Drug Metab Dispos. 2015 Nov;43(11):1646-54. (PMID: 26281846)
Nat Genet. 2018 Jun;50(6):825-833. (PMID: 29785013)
Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11952-7. (PMID: 23818646)
Genome Res. 2020 Jan;30(1):1-11. (PMID: 31852722)
Cell. 2016 Dec 15;167(7):1853-1866.e17. (PMID: 27984732)
Genome Res. 2017 Mar;27(3):393-406. (PMID: 28073919)
Nat Genet. 2019 Oct;51(10):1475-1485. (PMID: 31548722)
Stem Cell Reports. 2017 Aug 8;9(2):615-628. (PMID: 28757163)
Genome Res. 2016 Aug;26(8):1023-33. (PMID: 27311442)
Cell Stem Cell. 2019 Nov 7;25(5):713-727.e10. (PMID: 31631012)
Nat Biotechnol. 2018 Nov 19;:. (PMID: 30451991)
Nat Genet. 2015 Nov;47(11):1236-41. (PMID: 26414676)
Genome Res. 2020 Sep;30(9):1317-1331. (PMID: 32887689)
Brain. 2020 Mar 1;143(3):891-905. (PMID: 32129831)
Nat Methods. 2013 Aug;10(8):774-80. (PMID: 23852450)
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1291-E1300. (PMID: 28137873)
Mol Cell. 2017 Feb 16;65(4):604-617.e6. (PMID: 28212748)
Mol Psychiatry. 2018 Dec;23(12):2254-2265. (PMID: 29880880)
Nat Genet. 2018 May;50(5):668-681. (PMID: 29700475)
Biomacromolecules. 2013 May 13;14(5):1379-87. (PMID: 23514247)
Cell. 2020 Mar 19;180(6):1262-1271.e15. (PMID: 32169219)
Genome Res. 2016 Mar;26(3):397-405. (PMID: 26813977)
Dev Cell. 2018 Oct 8;47(1):38-52.e6. (PMID: 30300589)
Nat Commun. 2019 Jun 4;10(1):2434. (PMID: 31164647)
Genome Biol. 2020 Dec 8;21(1):298. (PMID: 33292397)
Nature. 2014 Jul 24;511(7510):421-7. (PMID: 25056061)
Nat Neurosci. 2020 Apr;23(4):510-519. (PMID: 32203495)
Genome Res. 2014 Oct;24(10):1595-602. (PMID: 25035418)
iScience. 2020 Mar 27;23(3):100888. (PMID: 32087575)
Nat Commun. 2018 Dec 19;9(1):5380. (PMID: 30568279)
Annu Rev Genet. 2017 Nov 27;51:171-194. (PMID: 28853924)
Mol Ther Nucleic Acids. 2019 Jun 7;16:637-649. (PMID: 31108320)
Nat Neurosci. 2018 Mar;21(3):447-454. (PMID: 29403034)
Genome Res. 2016 Feb;26(2):238-55. (PMID: 26576614)
Cell. 2019 Jan 24;176(3):549-563.e23. (PMID: 30661752)
Neuropsychopharmacology. 2020 Jun;45(7):1196-1206. (PMID: 32193514)
Nucleic Acids Res. 2017 Feb 28;45(4):e16. (PMID: 28204611)
Am J Hum Genet. 2014 Nov 6;95(5):535-52. (PMID: 25439723)
Nat Neurosci. 2021 Jul;24(7):941-953. (PMID: 34017130)
Nat Neurosci. 2018 Aug;21(8):1117-1125. (PMID: 30050107)
Biol Psychiatry. 2021 Jan 1;89(1):41-53. (PMID: 32736792)
Nature. 2015 Feb 19;518(7539):317-30. (PMID: 25693563)
Nature. 2017 Oct 11;550(7675):204-213. (PMID: 29022597)
EMBO Mol Med. 2020 May 8;12(5):e12112. (PMID: 32239644)
Genome Biol. 2020 Apr 6;21(1):90. (PMID: 32252787)
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5294-300. (PMID: 23479647)
Science. 2018 Dec 14;362(6420):. (PMID: 30545853)
Nat Genet. 2013 Jun;45(6):580-5. (PMID: 23715323)
Nat Neurosci. 2016 Nov;19(11):1442-1453. (PMID: 27668389)
Nature. 2012 Sep 6;489(7414):57-74. (PMID: 22955616)
Nat Genet. 2019 Jun;51(6):973-980. (PMID: 31133750)
Mol Cell. 2018 May 3;70(3):565. (PMID: 29727622)
Science. 2018 Dec 14;362(6420):. (PMID: 30545857)
Curr Biol. 2018 Jul 9;28(13):2103-2114.e5. (PMID: 30008330)
Genome Res. 2013 Nov;23(11):1908-15. (PMID: 23921661)
Sci Rep. 2016 Jun 24;6:28420. (PMID: 27341390)
Nat Neurosci. 2016 Dec;19(12):1743-1749. (PMID: 27798629)
Nat Neurosci. 2020 Apr;23(4):583-593. (PMID: 32152537)
Nat Commun. 2019 Jun 3;10(1):2396. (PMID: 31160561)
Nat Biotechnol. 2009 Dec;27(12):1173-5. (PMID: 19915551)
Nat Genet. 2018 Jul;50(7):956-967. (PMID: 29955180)
Cell. 2016 Oct 6;167(2):341-354.e12. (PMID: 27667684)
Nat Genet. 2019 Aug;51(8):1252-1262. (PMID: 31367015)
Nature. 2016 Feb 11;530(7589):177-83. (PMID: 26814963)
Genome Res. 2015 Aug;25(8):1206-14. (PMID: 26084464)
Nat Genet. 2018 Mar;50(3):381-389. (PMID: 29483656)
Cell. 2016 Jun 2;165(6):1519-1529. (PMID: 27259153)
Neuron. 2019 Oct 23;104(2):239-255.e12. (PMID: 31422865)
Sci Data. 2019 Sep 24;6(1):180. (PMID: 31551426)
Nature. 2009 Aug 6;460(7256):748-52. (PMID: 19571811)
Genome Biol. 2017 Nov 20;18(1):219. (PMID: 29151363)
Nat Rev Genet. 2016 Apr 12;17(6):353-64. (PMID: 27070863)
Genome Res. 2018 Oct;28(10):1520-1531. (PMID: 30158147)
J Neurosci. 2013 Feb 13;33(7):2732-53. (PMID: 23407934)
Science. 2018 Dec 14;362(6420):. (PMID: 30545854)
Nat Biotechnol. 2016 Nov;34(11):1180-1190. (PMID: 27701403)
Nat Genet. 2019 Jul;51(7):1160-1169. (PMID: 31253979)
Hum Mutat. 2019 Sep;40(9):1280-1291. (PMID: 31106481)
Nat Biotechnol. 2016 Feb;34(2):167-74. (PMID: 26807528)
Genome Res. 2012 Sep;22(9):1748-59. (PMID: 22955986)
Nat Commun. 2019 Jan 11;10(1):134. (PMID: 30635555)
Nat Methods. 2020 Nov;17(11):1083-1091. (PMID: 33046894)
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):. (PMID: 33372131)
Science. 2018 Dec 14;362(6420):. (PMID: 30545851)
Genome Res. 2019 Jun;29(6):896-906. (PMID: 31152051)
Nat Biotechnol. 2019 Jul;37(7):803-809. (PMID: 31267113)
Nat Genet. 2017 Dec;49(12):1747-1751. (PMID: 29058714)
Cell Rep. 2020 Dec 22;33(12):108531. (PMID: 33357440)
Nat Genet. 2019 Dec;51(12):1664-1669. (PMID: 31784727)
Science. 2018 Dec 14;362(6420):. (PMID: 30545856)
Mol Cell. 2018 Sep 20;71(6):1012-1026.e3. (PMID: 30174293)
Nat Neurosci. 2020 Feb;23(2):185-193. (PMID: 31932770)
BMC Genomics. 2019 Jun 20;20(1):511. (PMID: 31221079)
Science. 2020 Nov 27;370(6520):. (PMID: 33243861)
Elife. 2019 Sep 23;8:. (PMID: 31545165)
Am J Respir Crit Care Med. 2019 Jan 1;199(1):52-61. (PMID: 30079747)
Am J Hum Genet. 2018 Dec 6;103(6):874-892. (PMID: 30503521)
Genome Res. 2016 Jun;26(6):778-86. (PMID: 27197208)
Science. 2020 Sep 11;369(6509):. (PMID: 32913075)
Science. 2015 May 8;348(6235):648-60. (PMID: 25954001)
Cell. 2016 Aug 25;166(5):1269-1281.e19. (PMID: 27565349)
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19498-503. (PMID: 23129659)
Nat Struct Mol Biol. 2020 Sep;27(9):814-821. (PMID: 32719458)
Nat Genet. 2018 Jun;50(6):874-882. (PMID: 29785012)
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9158-63. (PMID: 20439748)
Trends Neurosci. 2019 Feb;42(2):115-127. (PMID: 30563709)
Science. 2013 Mar 1;339(6123):1074-7. (PMID: 23328393)
Elife. 2020 Feb 11;9:. (PMID: 32043966)
Cell. 2015 Oct 22;163(3):698-711. (PMID: 26496609)
Cell. 2020 Feb 6;180(3):568-584.e23. (PMID: 31981491)
Genome Med. 2020 Sep 11;12(1):79. (PMID: 32912286)
Science. 2019 Nov 29;366(6469):1134-1139. (PMID: 31727856)
Nat Neurosci. 2018 Mar;21(3):440-446. (PMID: 29335603)

P50 HD103525 United States HD NICHD NIH HHS; R01 MH116999 United States MH NIMH NIH HHS

Keywords: Enhancer; GWAS; Noncoding variants; Polygenicity; Reporter assay; UTR

Date Created: 20200827 Date Completed: 20210423 Latest Revision: 20241007

20241007

PMC7938388

10.1016/j.biopsych.2020.06.011

32843144