Human Gene Module / Chromosome 8 / MSRA

MSRAmethionine sulfoxide reductase A

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 13
Rare Variants / Common Variants
1 / 6
Aliases
MSRA, PMSR
Associated Syndromes
-
Chromosome Band
8p23.1
Associated Disorders
-
Relevance to Autism

A transcriptome-wide association study (TWAS) of 7,805 ASD proband-parent trios, which was subsequently replicated using 35,740 independent samples, using eQTL and splicing quantitative trait loci in 12 brain tissues from GTEx and the CommonMind Consortium (CMC) in Huang et al., 2021 identified MSRA as a gene whose transcriptome-wide association with ASD remained significant after a stringent Bonferroni correction for all genes and all tissues in the analysis (meta-analysis P-value 2.05E-07 in CMC DLPFC-splicing tissue). MSRA had previously been identified in Grove et al., 2019 as a gene that remained significant after Bonferroni correction following MAGMA gene-based association from the iPSYCH-PGC ASD meta analysis (P-value 1.63E-02). MSRA has been reported in several genome-wide meta-analyses as a candidate gene for schizophrenia (Goes et al., 2015; Li et al., 2017; Ikeda et al., 2018; Lam et al., 2019), while other association studies have identified MSRA as a candidate gene for bipolar disorder (Stahl et al., 2019), neuroticism (Fan et al., 2017; Nagel et al., 2018), and insomnia (Lane et al., 2019).

Molecular Function

This gene encodes a ubiquitous and highly conserved protein that carries out the enzymatic reduction of methionine sulfoxide to methionine. Human and animal studies have shown the highest levels of expression in kidney and nervous tissue. The protein functions in the repair of oxidatively damaged proteins to restore biological activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MSRA (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association - Walss-Bass C et al. (2009) No -
2 Positive Association - Goes FS et al. (2015) No -
3 Positive Association - Fan Q et al. (2017) No -
4 Positive Association Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia Li Z et al. (2017) No -
5 Positive Association - Nagel M et al. (2018) No -
6 Positive Association Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect Ikeda M et al. (2019) No -
7 Support Identification of common genetic risk variants for autism spectrum disorder Grove J , et al. (2019) Yes -
8 Positive Association - Lane JM et al. (2019) No -
9 Positive Association - Stahl EA et al. (2019) No -
10 Positive Association - Lam M et al. (2019) No -
11 Primary - Huang K et al. (2021) Yes -
12 Positive Association - Jung K et al. (2023) No -
13 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.211+1G>A - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.544-39333G>C;c.424-39333G>C;c.415-39333G>C - intron_variant - - - 30285260 Ikeda M et al. (2019)
c.332-15491G>A;c.212-15491G>A;c.203-15491G>A;c.134-15491G>A - intron_variant - - - 37258574 Jung K et al. (2023)
c.544-39333G>C;c.424-39333G>C;c.415-39333G>C - intron_variant - - - 28991256 Li Z et al. (2017)
.543+48856C>T;c.423+48856C>T;c.414+48856C>T - intron_variant - - - 31740837 Lam M et al. (2019)
c.143-31918A>T;c.14-31918A>T;c.-56-31918A>T - intron_variant - - - 26198764 Goes FS et al. (2015)
c.143-31918A>T;c.14-31918A>T;c.-56-31918A>T - intron_variant - - - 30285260 Ikeda M et al. (2019)
SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.47400344531614

Ranking 8704/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 1.6997610030306E-6

Ranking 14865/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94453633343621

Ranking 16114/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.47082205574242

Ranking 741/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with MSRA(1 CNVs)
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8p23.1 49 Deletion-Duplication 72  /  445
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