Evaluating the Association Between Genetically Proxied Neurodevelopmental Language Phenotypes and the Risk of Primary Progressive Aphasia.
Journal
Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060
Informations de publication
Date de publication:
02 05 2023
02 05 2023
Historique:
received:
26
08
2022
accepted:
18
01
2023
pmc-release:
02
05
2024
medline:
3
5
2023
pubmed:
9
3
2023
entrez:
8
3
2023
Statut:
ppublish
Résumé
Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations. Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results. Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype ( Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (
Sections du résumé
BACKGROUND AND OBJECTIVES
Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations.
METHODS
Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results.
RESULTS
Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (
DISCUSSION
Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (
Identifiants
pubmed: 36889925
pii: WNL.0000000000207136
doi: 10.1212/WNL.0000000000207136
pmc: PMC10159766
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1922-e1929Subventions
Organisme : NIA NIH HHS
ID : P30 AG013854
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG077444
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072980
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072977
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG019610
Pays : United States
Informations de copyright
© 2023 American Academy of Neurology.
Références
Lab Invest. 2019 Jul;99(7):912-928
pubmed: 30742061
Elife. 2018 May 30;7:
pubmed: 29846171
Cereb Cortex. 2021 Jul 29;31(9):4151-4168
pubmed: 33836062
Neurology. 2011 Mar 15;76(11):1006-14
pubmed: 21325651
Lancet Neurol. 2012 Jun;11(6):545-55
pubmed: 22608668
NPJ Genom Med. 2021 Jul 27;6(1):64
pubmed: 34315907
Brain. 2022 Jun 30;145(6):2133-2148
pubmed: 35441216
Arch Neurol. 2008 Feb;65(2):244-8
pubmed: 18268195
Brain. 2019 Oct 1;142(10):2938-2947
pubmed: 31504236
Nat Hum Behav. 2021 Jan;5(1):59-70
pubmed: 32989287
Mol Psychiatry. 2020 Nov;25(11):2942-2951
pubmed: 30514930
Lancet Neurol. 2014 Jul;13(7):686-99
pubmed: 24943344
BMJ. 2018 Jul 12;362:k601
pubmed: 30002074
Brain. 2011 Sep;134(Pt 9):2456-77
pubmed: 21810890
J Neurol. 2019 Aug;266(8):2075-2086
pubmed: 31119452
Adv Exp Med Biol. 2021;1281:33-49
pubmed: 33433867
BMJ. 2021 Oct 26;375:n2233
pubmed: 34702754
Annu Rev Genomics Hum Genet. 2015;16:327-50
pubmed: 25939054
Sci Rep. 2015 May 05;5:9964
pubmed: 25944224
Ann Neurol. 2001 Apr;49(4):425-32
pubmed: 11310619
Brain Lang. 2013 Nov;127(2):135-8
pubmed: 23489582
Nat Genet. 2022 Nov;54(11):1621-1629
pubmed: 36266505
Brain. 2013 Nov;136(Pt 11):3461-73
pubmed: 24056533
Neurology. 1998 Dec;51(6):1546-54
pubmed: 9855500
Neurology. 2020 Aug 18;95(7):e847-e855
pubmed: 32699140
Brain Commun. 2019;1(1):fcz027
pubmed: 32699834
Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):
pubmed: 34785596
Nat Hum Behav. 2021 Sep;5(9):1226-1239
pubmed: 33723403
Nat Rev Mol Cell Biol. 2019 Jan;20(1):38-54
pubmed: 30323238
Nat Rev Neurol. 2014 Oct;10(10):554-69
pubmed: 25179257
Neurology. 1984 Jul;34(7):939-44
pubmed: 6610841
Arch Neurol. 2004 Feb;61(2):265-8
pubmed: 14967776
Wellcome Open Res. 2019 Nov 26;4:186
pubmed: 32760811