Human Gene Module / Chromosome 6 / CNR1

CNR1cannabinoid receptor 1 (brain)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 8
Rare Variants / Common Variants
22 / 4
Aliases
CNR1, CB1,  CNR,  CB-R,  CB1A,  CANN6,  CB1K5
Associated Syndromes
-
Chromosome Band
6q15
Associated Disorders
ASD
Relevance to Autism

Genetic association has been found between the CNR1 gene and striatal response to happy faces in a Caucasian cohort (Chakrabarti et al., 2006).

Molecular Function

The encoded protein has cannabinoid receptor activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CNR1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons Katona I , et al. (1999) No -
2 Primary Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces Chakrabarti B , et al. (2006) No ASD
3 Recent Recommendation Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission Domenici MR , et al. (2006) No -
4 Recent Recommendation Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis Schuchmann S , et al. (2006) No -
5 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
6 Support Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans Smith DR , et al. (2017) No -
7 Support - Zhou X et al. (2022) Yes -
8 Highly Cited Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice Ledent C , et al. (1999) No -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Simplex 23375656 Girirajan S , et al. (2013)
c.871G>A p.Val291Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.20G>A p.Gly7Asp missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.80A>G p.Asp27Gly missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.169C>G p.Pro57Ala missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.277G>A p.Glu93Lys missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.443G>A p.Arg148His missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.581G>C p.Gly194Ala missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.622T>C p.Phe208Leu missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.725C>T p.Thr242Ile missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.745G>A p.Val249Met missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.916G>A p.Val306Ile missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
c.1015A>G p.Ile339Val missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.1225C>T p.Arg409Trp missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.1256C>A p.Ala419Glu missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.1278G>T p.Met426Ile missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.1306G>A p.Ala436Thr missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.1348A>G p.Ile450Val missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
c.1357A>G p.Thr453Ala missense_variant Unknown - - 29145497 Smith DR , et al. (2017)
- - copy_number_gain Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1359G>A;c.1260G>A;c.1176G>A p.(=) synonymous_variant - - - 16623851 Chakrabarti B , et al. (2006)
c.-206-7128T>C;c.-63-9597T>C;c.-64+8023T>C;c.-79-9597T>C - intron_variant - - - 16623851 Chakrabarti B , et al. (2006)
c.-206-1198A>G;c.-63-3667A>G;c.-1452A>G;c.-79-3667A>G N/A intron_variant, 2KB_upstream_variant - - - 16623851 Chakrabarti B , et al. (2006)
c.-207+2592A>C;c.-207+1046A>C;c.-64+2536A>C;c.-64+2592A>C;c.-318A>C;c.-80+2592A>C;c.-64+3365A>C - intron_variant - - - 16623851 Chakrabarti B , et al. (2006)
SFARI Gene score
2

Strong Candidate

Genetic association has been found between the CNR1 gene and striatal response to happy faces in a Caucasian cohort (Chakrabarti et al., 2006). Seven exon-disrupting duplications involving the CNR1 gene were observed in a cohort of 2,588 cases compared to 1 exon-disrupting CNV in 2670 controls (p=0.032) (PMID 23375656). Screening for rare genetic variants in core endocannabinoid system genes in 6,032 patients with a broad spectrum of neurological disorders determined that heterozygous rare coding variants in CNR1 were significantly associated with pain sensitivity, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls (Smith et al., 2017).

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

Genetic association has been found between the CNR1 gene and striatal response to happy faces in a Caucasian cohort (Chakrabarti et al., 2006). Seven exon-disrupting duplications involving the CNR1 gene were observed in a cohort of 2,588 cases compared to 1 exon-disrupting CNV in 2670 controls (p=0.032) (PMID 23375656). Screening for rare genetic variants in core endocannabinoid system genes in 6,032 patients with a broad spectrum of neurological disorders determined that heterozygous rare coding variants in CNR1 were significantly associated with pain sensitivity, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls (Smith et al., 2017).

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Genetic association has been found between the CNR1 gene and striatal response to happy faces in a Caucasian cohort (Chakrabarti et al., 2006). Seven exon-disrupting duplications involving the CNR1 gene were observed in a cohort of 2,588 cases compared to 1 exon-disrupting CNV in 2670 controls (p=0.032) (PMID 23375656). Screening for rare genetic variants in core endocannabinoid system genes in 6,032 patients with a broad spectrum of neurological disorders determined that heterozygous rare coding variants in CNR1 were significantly associated with pain sensitivity, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls (Smith et al., 2017).

Reports Added
[Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.2017]
7/1/2015
icon
3

Increased from to 3

Description

Genetic association has been found between the CNR1 gene and striatal response to happy faces in a Caucasian cohort (Chakrabarti et al., 2006). Seven exon-disrupting duplications involving the CNR1 gene were observed in ASD probands from the Simons Simplex Collection compared to 1 exon-disrupting CNV in 2670 controls (p=0.032) (PMID 23375656).

Krishnan Probability Score

Score 0.76566157059786

Ranking 10/25841 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 0.15507222177208

Ranking 7348/18225 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 0.87380286904611

Ranking 4496/18665 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 7

Ranking 242/461 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 0.55616775021604

Ranking 220/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
HTR2A 5-hydroxytryptamine (serotonin) receptor 2A, G protein-coupled Human Protein Binding 3356 P28223
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