Human Gene Module / Chromosome 7 / PON1

PON1paraoxonase 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
1 / 5
Rare Variants / Common Variants
0 / 2
Aliases
PON1, ESA,  PON
Associated Syndromes
-
Chromosome Band
7q21.3
Associated Disorders
-
Relevance to Autism

Genetic association has been found between the PON1 gene and autism in the Caucasian-American population (D'Amelio et al., 2005).

Molecular Function

The encoded protein hydrolyzes a broad spectrum of organophosphate substrates and a number of aromatic carboxylic acid esters.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PON1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities Aviram M , et al. (2000) No -
2 Primary Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions D'Amelio M , et al. (2005) Yes -
3 Recent Recommendation High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism Paca SP , et al. (2005) No -
4 Recent Recommendation A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS Wills AM , et al. (2009) No -
5 Recent Recommendation Decreased serum arylesterase activity in autism spectrum disorders Gaita L , et al. (2010) No -
Rare Variants  

No rare variants reported.

Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.163T>C p.Leu55Met missense_variant - - - 16027737 D'Amelio M , et al. (2005)
c.575A>G p.Gln192Arg missense_variant - - - 16027737 D'Amelio M , et al. (2005)
SFARI Gene score
2

Strong Candidate

Initial association study was negative (PMID: 15446388). Second study hypothesized that higher use of organophosphates would make an association more likely in US than European populations (PMID: 16027737), observed marginal association in US population, but none in European. Low PON esterase activity observed in autistic children (PMID: 16297937), but small n (12 case, 9 controls) and marginal significance. In a second larger study (n=50 case, 30 controls) (PMID: 18624774) both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with the Q192R and L55M polymorphisms in the PON1 gene. In largest study to date (PMID: 20488557) arylesterase, but not diazoxonase activity, was significantly decreased in 174 ASD patients compared to 175 first-degree relatives and 144 controls (P = 2.65E10-16). Also serum arylesterase activity, in combination with PON1 genotypes at two single nucleotide polymorphisms (SNPs) known to influence protein amounts (rs705379: C-108T) and substrate specificity (rs662: Q192R), was able to discriminate ASD patients from controls with elevated sensitivity and specificity, depending on genotype and ethnic group.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We 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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Initial association study was negative (PMID: 15446388). Second study hypothesized that higher use of organophosphates would make an association more likely in US than European populations (PMID: 16027737), observed marginal association in US population, but none in European. Low PON esterase activity observed in autistic children (PMID: 16297937), but small n (12 case, 9 controls) and marginal significance. In a second larger study (n=50 case, 30 controls) (PMID: 18624774) both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with the Q192R and L55M polymorphisms in the PON1 gene. In largest study to date (PMID: 20488557) arylesterase, but not diazoxonase activity, was significantly decreased in 174 ASD patients compared to 175 first-degree relatives and 144 controls (P = 2.65E10-16). Also serum arylesterase activity, in combination with PON1 genotypes at two single nucleotide polymorphisms (SNPs) known to influence protein amounts (rs705379: C-108T) and substrate specificity (rs662: Q192R), was able to discriminate ASD patients from controls with elevated sensitivity and specificity, depending on genotype and ethnic group.

Reports Added
[New Scoring Scheme]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

Initial association study was negative (PMID: 15446388). Second study hypothesized that higher use of organophosphates would make an association more likely in US than European populations (PMID: 16027737), observed marginal association in US population, but none in European. Low PON esterase activity observed in autistic children (PMID: 16297937), but small n (12 case, 9 controls) and marginal significance. In a second larger study (n=50 case, 30 controls) (PMID: 18624774) both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with the Q192R and L55M polymorphisms in the PON1 gene. In largest study to date (PMID: 20488557) arylesterase, but not diazoxonase activity, was significantly decreased in 174 ASD patients compared to 175 first-degree relatives and 144 controls (P = 2.65 ? 10?16). Also serum arylesterase activity, in combination with PON1 genotypes at two single nucleotide polymorphisms (SNPs) known to influence protein amounts (rs705379: C-108T) and substrate specificity (rs662: Q192R), was able to discriminate ASD patients from controls with elevated sensitivity and specificity, depending on genotype and ethnic group.

4/1/2014
No data
icon
3

Increased from No data to 3

Description

Initial association study was negative (PMID: 15446388). Second study hypothesized that higher use of organophosphates would make an association more likely in US than European populations (PMID: 16027737), observed marginal association in US population, but none in European. Low PON esterase activity observed in autistic children (PMID: 16297937), but small n (12 case, 9 controls) and marginal significance. In a second larger study (n=50 case, 30 controls) (PMID: 18624774) both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with the Q192R and L55M polymorphisms in the PON1 gene. In largest study to date (PMID: 20488557) arylesterase, but not diazoxonase activity, was significantly decreased in 174 ASD patients compared to 175 first-degree relatives and 144 controls (P = 2.65 ? 10?16). Also serum arylesterase activity, in combination with PON1 genotypes at two single nucleotide polymorphisms (SNPs) known to influence protein amounts (rs705379: C-108T) and substrate specificity (rs662: Q192R), was able to discriminate ASD patients from controls with elevated sensitivity and specificity, depending on genotype and ethnic group.

Krishnan Probability Score

Score 0.49246731369502

Ranking 4521/25841 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 0.0022088441733079

Ranking 11204/18225 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 0.94540579899537

Ranking 16457/18665 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
Larsen Cumulative Evidence Score

Score 6

Ranking 266/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.00071678523510699

Ranking 8720/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
MPO myeloperoxidase Human Protein Binding 4353 P05164
PON3 Serum paraoxonase/lactonase 3 Human Protein Binding 5446 Q15166
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