MACROD2MACRO domain containing 2
Autism Reports / Total Reports
14 / 22Rare Variants / Common Variants
7 / 12Aliases
MACROD2, C20orf133Associated Syndromes
-Chromosome Band
20p12.1Associated Disorders
ADHDRelevance to Autism
Genetic association has been found between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
Molecular Function
The protein encoded by this gene is a deacetylase involved in removing ADP-ribose from mono-ADP-ribosylated proteins. The encoded protein has been shown to translocate from the nucleus to the cytoplasm upon DNA damage.
External Links
SFARI Genomic Platforms
Reports related to MACROD2 (22 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | The C20orf133 gene is disrupted in a patient with Kabuki syndrome | Maas NM , et al. (2007) | No | - |
| 2 | Recent Recommendation | Lack of C20orf133 and FLRT3 mutations in 43 patients with Kabuki syndrome in Japan | Kuniba H , et al. (2008) | No | - |
| 3 | Recent Recommendation | Hotspots of large rare deletions in the human genome | Bradley WE , et al. (2010) | No | - |
| 4 | Primary | A genome-wide scan for common alleles affecting risk for autism | Anney R , et al. (2010) | Yes | - |
| 5 | Recent Recommendation | Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases | Chen D , et al. (2011) | No | - |
| 6 | Negative Association | No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder | Curran S , et al. (2011) | Yes | - |
| 7 | Support | Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism | Lesca G , et al. (2012) | No | ADHD |
| 8 | Negative Association | The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families | Prandini P , et al. (2012) | Yes | - |
| 9 | Positive Association | Individual common variants exert weak effects on the risk for autism spectrum disorders | Anney R , et al. (2012) | Yes | - |
| 10 | Support | A discovery resource of rare copy number variations in individuals with autism spectrum disorder | Prasad A , et al. (2013) | Yes | - |
| 11 | Recent Recommendation | Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity | Jahanshad N , et al. (2013) | No | - |
| 12 | Support | Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families | Egger G , et al. (2014) | Yes | - |
| 13 | Positive Association | MACROD2 gene associated with autistic-like traits in a general population sample | Jones RM , et al. (2014) | No | - |
| 14 | Positive Association | Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis | Namjou B , et al. (2014) | Yes | - |
| 15 | Positive Association | Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population | Kuo PH , et al. (2015) | Yes | - |
| 16 | Negative Association | Lack of replication of previous autism spectrum disorder GWAS hits in European populations | Torrico B , et al. (2016) | Yes | - |
| 17 | Positive Association | Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia | Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) | Yes | - |
| 18 | Recent recommendation | Biochemical and Morphological Characterization of a Neurodevelopmental Disorder-Related Mono-ADP-Ribosylhydrolase, MACRO Domain Containing 2 | Ito H , et al. (2018) | No | - |
| 19 | Recent Recommendation | Identification of common genetic risk variants for autism spectrum disorder | Grove J , et al. (2019) | Yes | - |
| 20 | Positive Association | Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism | Matoba N et al. (2020) | Yes | - |
| 21 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
| 22 | Support | - | Zhou X et al. (2022) | Yes | - |
Rare Variants (7)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | copy_number_loss | Unknown | - | - | 24643514 | Egger G , et al. (2014) | |
| - | - | copy_number_loss | Unknown | - | Unknown | 23275889 | Prasad A , et al. (2013) | |
| - | - | copy_number_gain | Familial | Paternal | Unknown | 22738016 | Lesca G , et al. (2012) | |
| - | - | copy_number_loss | Familial | Paternal | Unknown | 22738016 | Lesca G , et al. (2012) | |
| c.467C>T | p.Ser156Phe | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.965G>A | p.Arg322His | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.543A>G | p.Ala181%3D | synonymous_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) |
Common Variants (12)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.418+79618A>C | - | intron_variant | - | - | - | 28540026 | Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) | |
| c.418+177262A>T | - | intron_variant | - | - | - | 28540026 | Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) | |
| c.164-19716G>A | - | intron_variant | - | - | - | 26398136 | Kuo PH , et al. (2015) | |
| c.418+95142C>T | - | intron_variant | - | - | - | 32747698 | Matoba N et al. (2020) | |
| c.418+81866T>C | A | intron_variant | - | - | - | 20663923 | Anney R , et al. (2010) | |
| c.418+197367C>T | - | intron_variant | - | - | - | 22843504 | Anney R , et al. (2012) | |
| c.418+199551T>C | - | intron_variant | - | - | - | 22843504 | Anney R , et al. (2012) | |
| c.418+201817G>T | - | intron_variant | - | - | - | 22843504 | Anney R , et al. (2012) | |
| c.418+243136C>T | - | intron_variant | - | - | - | 25477900 | Namjou B , et al. (2014) | |
| c.418+81866T>C | C/T | intron_variant | - | - | - | 21656903 | Curran S , et al. (2011) | |
| c.418+81866T>C | Effect allele, T | intron_variant | - | - | - | 25360606 | Jones RM , et al. (2014) | |
| c.418+170662_418+170668delTTTTTTT | - | intron_variant | - | - | - | 30804558 | Grove J , et al. (2019) |
SFARI Gene score
Strong Candidate
A polymorphism in the MACROD2 gene (rs4141463) reached genome-wide significance (P = 2.1 x 10-8) in a primary association analysis of 1558 ASD families from the Autism Genome Project in Anney et al., 2010; analysis of a smaller replication sample demonstrated that while this risk allele was again over-transmitted, its effect size in the replication sample was smaller, and the association signal fell below the genome-wide association significance threshold (P < 5.0 x 10-8) in combined samples. However, genome-wide association significance between the rs4141463 risk allele of MACROD2 and autism was not replicated in a large European case-control cohort in Curran et al., 2011. Other polymorphisms in the MACROD2 gene have been shown to associate with ASD or autistic-like traits in the general population in subsequent studies (Anney et al., 2012; Jones et al., 2014; Namjou et al., 2014; Kuo et al., 2015; Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017), although the association signals in these studies failed to reach genome-wide significance. A genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls in Grove et al., 2019 identified an intronic SNP in MACROD2 (rs71190516) as the index variant for a genome-wide significance locus (P = 2.75 x 10-8); MACROD2 was the only protein-coding gene within this locus.
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
7/1/2020
Score remained at 2
Description
A polymorphism in the MACROD2 gene (rs4141463) reached genome-wide significance (P = 2.1 x 10-8) in a primary association analysis of 1558 ASD families from the Autism Genome Project in Anney et al., 2010; analysis of a smaller replication sample demonstrated that while this risk allele was again over-transmitted, its effect size in the replication sample was smaller, and the association signal fell below the genome-wide association significance threshold (P < 5.0 x 10-8) in combined samples. However, genome-wide association significance between the rs4141463 risk allele of MACROD2 and autism was not replicated in a large European case-control cohort in Curran et al., 2011. Other polymorphisms in the MACROD2 gene have been shown to associate with ASD or autistic-like traits in the general population in subsequent studies (Anney et al., 2012; Jones et al., 2014; Namjou et al., 2014; Kuo et al., 2015; Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017), although the association signals in these studies failed to reach genome-wide significance. A genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls in Grove et al., 2019 identified an intronic SNP in MACROD2 (rs71190516) as the index variant for a genome-wide significance locus (P = 2.75 x 10-8); MACROD2 was the only protein-coding gene within this locus.
10/1/2019
Score remained at 2
New Scoring Scheme
Description
A polymorphism in the MACROD2 gene (rs4141463) reached genome-wide significance (P = 2.1 x 10-8) in a primary association analysis of 1558 ASD families from the Autism Genome Project in Anney et al., 2010; analysis of a smaller replication sample demonstrated that while this risk allele was again over-transmitted, its effect size in the replication sample was smaller, and the association signal fell below the genome-wide association significance threshold (P < 5.0 x 10-8) in combined samples. However, genome-wide association significance between the rs4141463 risk allele of MACROD2 and autism was not replicated in a large European case-control cohort in Curran et al., 2011. Other polymorphisms in the MACROD2 gene have been shown to associate with ASD or autistic-like traits in the general population in subsequent studies (Anney et al., 2012; Jones et al., 2014; Namjou et al., 2014; Kuo et al., 2015; Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017), although the association signals in these studies failed to reach genome-wide significance. A genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls in Grove et al., 2019 identified an intronic SNP in MACROD2 (rs71190516) as the index variant for a genome-wide significance locus (P = 2.75 x 10-8); MACROD2 was the only protein-coding gene within this locus.
Reports Added
[New Scoring Scheme]1/1/2019
Decreased from 3 to 2
Description
A polymorphism in the MACROD2 gene (rs4141463) reached genome-wide significance (P = 2.1 x 10-8) in a primary association analysis of 1558 ASD families from the Autism Genome Project in Anney et al., 2010; analysis of a smaller replication sample demonstrated that while this risk allele was again over-transmitted, its effect size in the replication sample was smaller, and the association signal fell below the genome-wide association significance threshold (P < 5.0 x 10-8) in combined samples. However, genome-wide association significance between the rs4141463 risk allele of MACROD2 and autism was not replicated in a large European case-control cohort in Curran et al., 2011. Other polymorphisms in the MACROD2 gene have been shown to associate with ASD or autistic-like traits in the general population in subsequent studies (Anney et al., 2012; Jones et al., 2014; Namjou et al., 2014; Kuo et al., 2015; Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017), although the association signals in these studies failed to reach genome-wide significance. A genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls in Grove et al., 2019 identified an intronic SNP in MACROD2 (rs71190516) as the index variant for a genome-wide significance locus (P = 2.75 x 10-8); MACROD2 was the only protein-coding gene within this locus.
10/1/2018
Decreased from 3 to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
4/1/2017
Decreased from 3 to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
Reports Added
[MACROD2 gene associated with autistic-like traits in a general population sample.2014] [A genome-wide scan for common alleles affecting risk for autism.2010] [No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.2011] [The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families.2012] [Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos...2014] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [The C20orf133 gene is disrupted in a patient with Kabuki syndrome.2007] [Lack of C20orf133 and FLRT3 mutations in 43 patients with Kabuki syndrome in Japan.2008] [Hotspots of large rare deletions in the human genome.2010] [Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.2011] [Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity.2013] [Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.2015] [Lack of replication of previous autism spectrum disorder GWAS hits in European populations.2016] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]7/1/2016
Decreased from 3 to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
1/1/2016
Decreased from 3 to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
Reports Added
[MACROD2 gene associated with autistic-like traits in a general population sample.2014] [A genome-wide scan for common alleles affecting risk for autism.2010] [No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.2011] [The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families.2012] [Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos...2014] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [The C20orf133 gene is disrupted in a patient with Kabuki syndrome.2007] [Lack of C20orf133 and FLRT3 mutations in 43 patients with Kabuki syndrome in Japan.2008] [Hotspots of large rare deletions in the human genome.2010] [Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.2011] [Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity.2013] [Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.2015]1/1/2015
Decreased from 3 to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
7/1/2014
Increased from No data to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
4/1/2014
Increased from No data to 3
Description
Inconsistent genetic association has been reported between the MACROD2 gene and autism in AGP, AGRE and SAGE cohorts (Anney et al., 2010). However, genetic association was not found between MACROD2 and autism in a large European population cohort (Curran et al., 2011).
Krishnan Probability Score
Score 0.49479938016342
Ranking 3418/25841 scored genes
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ExAC Score
Score 0.011356747021034
Ranking 9904/18225 scored genes
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Sanders TADA Score
Score 0.95078348633128
Ranking 18627/18665 scored genes
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Larsen Cumulative Evidence Score
Score 33
Ranking 66/461 scored genes
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Zhang D Score
Score -0.24859005982104
Ranking 16353/20870 scored genes
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