PMID- 35042540
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20240405
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 14
IP  - 1
DP  - 2022 Jan 19
TI  - Functional characterisation of the amyotrophic lateral sclerosis risk locus 
      GPX3/TNIP1.
PG  - 7
LID - 10.1186/s13073-021-01006-6 [doi]
LID - 7
AB  - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, 
      neurodegenerative disease with a genetic contribution to disease liability. 
      Genome-wide association studies (GWAS) have identified ten risk loci to date, 
      including the TNIP1/GPX3 locus on chromosome five. Given association analysis 
      data alone cannot determine the most plausible risk gene for this locus, we 
      undertook a comprehensive suite of in silico, in vivo and in vitro studies to 
      address this. METHODS: The Functional Mapping and Annotation (FUMA) pipeline and 
      five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage 
      Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), 
      Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide 
      association study (TWAS) analyses) were used to perform bioinformatic integration 
      of GWAS data (N(cases) = 20,806, N(controls) = 59,804) with 'omics reference 
      datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 
      2581). This was followed up by specific expression studies in ALS case-control 
      cohorts (microarray N(total) = 942, protein N(total) = 300) and gene knockdown 
      (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). 
      RESULTS: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 x 10(-6)), but 
      there was no simple SNP/expression relationship. Integrating multiple datasets 
      using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood 
      in ALS cases identified that lower GPX3 expression correlated with a more 
      progressed disease (ALS functional rating score, p = 5.5 x 10(-3), adjusted R(2) 
      = 0.042, B(effect) = 27.4 +/- 13.3 ng/ml/ALSFRS unit) with microarray and protein 
      data suggesting lower expression with risk allele (recessive model p = 0.06, p = 
      0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor 
      deficits in zebrafish-MO (mean difference vs. control +/- 95% CI, vs. control, swim 
      distance = 112 +/- 28 mm, time = 1.29 +/- 0.59 s, speed = 32.0 +/- 2.53 mm/s, 
      respectively, p for all < 0.0001), which were rescued with gpx3 expression, with 
      no phenotype identified with tnip1 KD or gpx3 overexpression. CONCLUSIONS: These 
      results support GPX3 as a lead ALS risk gene in this locus, with more data needed 
      to confirm/reject a role for TNIP1. This has implications for understanding 
      disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established 
      ALS-associated gene) and identifying new therapeutic approaches. Few previous 
      examples of in-depth investigations of risk loci in ALS exist and a similar 
      approach could be applied to investigate future expected GWAS findings.
CI  - (c) 2021. The Author(s).
FAU - Restuadi, Restuadi
AU  - Restuadi R
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Steyn, Frederik J
AU  - Steyn FJ
AD  - School of Biomedical Sciences, The University of Queensland, QLD, Brisbane, 4072, 
      Australia.
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, QLD, Brisbane, 
      4029, Australia.
AD  - Centre for Clinical Research, The University of Queensland, QLD, Brisbane, 4019, 
      Australia.
FAU - Kabashi, Edor
AU  - Kabashi E
AD  - Imagine Institute, Institut National de la Sante et de la Recherche Medicale 
      (INSERM) Unite 1163, Paris Descartes Universite, 75015, Paris, France.
AD  - Sorbonne Universite, Universite Pierre et Marie Curie (UPMC), Universite de Paris 
      06, INSERM Unite 1127, Centre National de la Recherche Scientifique (CNRS) Unite 
      Mixte de Recherche 7225, Institut du Cerveau et de la Moelle Epiniere (ICM), 
      75013, Paris, France.
FAU - Ngo, Shyuan T
AU  - Ngo ST
AD  - Centre for Clinical Research, The University of Queensland, QLD, Brisbane, 4019, 
      Australia.
AD  - Queensland Brain Institute, The University of Queensland, QLD, Brisbane, 4072, 
      Australia.
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, QLD, Brisbane, 4072, Australia.
FAU - Cheng, Fei-Fei
AU  - Cheng FF
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Nabais, Marta F
AU  - Nabais MF
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
AD  - University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, 
      Barrack Road, Exeter, EX2 5DW, UK.
FAU - Thompson, Mike J
AU  - Thompson MJ
AD  - Department of Computer Science, University of California Los Angeles, Los 
      Angeles, CA, USA.
AD  - Department of Bioinformatics, University of California Los Angeles, Los Angeles, 
      CA, USA.
FAU - Qi, Ting
AU  - Qi T
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Wu, Yang
AU  - Wu Y
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Henders, Anjali K
AU  - Henders AK
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Wallace, Leanne
AU  - Wallace L
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Bye, Chris R
AU  - Bye CR
AD  - Florey Institute for Neuroscience and Mental Health, University of Melbourne, 
      Melbourne, VIC, 3052, Australia.
FAU - Turner, Bradley J
AU  - Turner BJ
AD  - Florey Institute for Neuroscience and Mental Health, University of Melbourne, 
      Melbourne, VIC, 3052, Australia.
FAU - Ziser, Laura
AU  - Ziser L
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Mathers, Susan
AU  - Mathers S
AD  - Calvary Health Care Bethlehem, Parkdale, VIC, 3195, Australia.
FAU - McCombe, Pamela A
AU  - McCombe PA
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, QLD, Brisbane, 
      4029, Australia.
AD  - Centre for Clinical Research, The University of Queensland, QLD, Brisbane, 4019, 
      Australia.
FAU - Needham, Merrilee
AU  - Needham M
AD  - Fiona Stanley Hospital, Perth, WA, 6150, Australia.
AD  - Notre Dame University, Fremantle, WA, 6160, Australia.
AD  - Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, 
      6150, Australia.
FAU - Schultz, David
AU  - Schultz D
AD  - Department of Neurology, Flinders Medical Centre, Bedford Park, SA, 5042, 
      Australia.
FAU - Kiernan, Matthew C
AU  - Kiernan MC
AD  - Brain & Mind Centre, University of Sydney, Institute of Clinical Neurosciences, 
      Royal Prince Alfred Hospital, Sydney, NSW, 2006, Australia.
FAU - van Rheenen, Wouter
AU  - van Rheenen W
AD  - Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht 
      University, Utrecht, The Netherlands.
FAU - van den Berg, Leonard H
AU  - van den Berg LH
AD  - Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht 
      University, Utrecht, The Netherlands.
FAU - Veldink, Jan H
AU  - Veldink JH
AD  - Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht 
      University, Utrecht, The Netherlands.
FAU - Ophoff, Roel
AU  - Ophoff R
AD  - Department of Computer Science, University of California Los Angeles, Los 
      Angeles, CA, USA.
AD  - Department of Bioinformatics, University of California Los Angeles, Los Angeles, 
      CA, USA.
FAU - Gusev, Alexander
AU  - Gusev A
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical 
      School, Boston, MA, USA.
AD  - Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
FAU - Zaitlen, Noah
AU  - Zaitlen N
AD  - Department of Computer Science, University of California Los Angeles, Los 
      Angeles, CA, USA.
AD  - Department of Bioinformatics, University of California Los Angeles, Los Angeles, 
      CA, USA.
AD  - Department of Neurology, University of California Los Angeles, Los Angeles, CA, 
      90095, USA.
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      CA, 94158, USA.
FAU - McRae, Allan F
AU  - McRae AF
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
FAU - Henderson, Robert D
AU  - Henderson RD
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, QLD, Brisbane, 
      4029, Australia.
AD  - Centre for Clinical Research, The University of Queensland, QLD, Brisbane, 4019, 
      Australia.
AD  - Queensland Brain Institute, The University of Queensland, QLD, Brisbane, 4072, 
      Australia.
FAU - Wray, Naomi R
AU  - Wray NR
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia.
AD  - Queensland Brain Institute, The University of Queensland, QLD, Brisbane, 4072, 
      Australia.
FAU - Giacomotto, Jean
AU  - Giacomotto J
AD  - Queensland Brain Institute, The University of Queensland, QLD, Brisbane, 4072, 
      Australia.
AD  - Queensland Centre for Mental Health Research, West Moreton Hospital and Health 
      Service, Wacol, QLD, 4076, Australia.
FAU - Garton, Fleur C
AU  - Garton FC
AUID- ORCID: 0000-0002-1490-5930
AD  - Institute for Molecular Bioscience, The University of Queensland, QLD, Brisbane, 
      4072, Australia. f.garton@uq.edu.au.
LA  - eng
GR  - R01 MH115676/MH/NIMH NIH HHS/United States
GR  - T32 HG002536/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220119
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
SB  - IM
MH  - *Amyotrophic Lateral Sclerosis/genetics
MH  - Animals
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study/methods
MH  - Humans
MH  - *Neurodegenerative Diseases
MH  - Polymorphism, Single Nucleotide
MH  - Zebrafish/genetics
PMC - PMC8767698
OTO - NOTNLM
OT  - Computational biology
OT  - Disease progression
OT  - Genes
OT  - Genome-wide association study
OT  - MND
OT  - Motor neurone disease
OT  - Neurodegenerative diseases
OT  - Quantitative trait loci
OT  - Regulator
OT  - Zebrafish
COIS- The authors declare that they have no competing interests.
EDAT- 2022/01/20 06:00
MHDA- 2022/03/17 06:00
PMCR- 2022/01/19
CRDT- 2022/01/19 05:48
PHST- 2021/03/06 00:00 [received]
PHST- 2021/11/30 00:00 [accepted]
PHST- 2022/01/19 05:48 [entrez]
PHST- 2022/01/20 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2022/01/19 00:00 [pmc-release]
AID - 10.1186/s13073-021-01006-6 [pii]
AID - 1006 [pii]
AID - 10.1186/s13073-021-01006-6 [doi]
PST - epublish
SO  - Genome Med. 2022 Jan 19;14(1):7. doi: 10.1186/s13073-021-01006-6.