Human Gene Module / Chromosome 12 / VDR

VDRvitamin D receptor

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
10 / 10
Rare Variants / Common Variants
0 / 12
Aliases
VDR, NR1I1,  PPP1R163
Associated Syndromes
-
Genetic Category
Genetic Association, Functional
Chromosome Band
12q13.11
Associated Disorders
-
Relevance to Autism

Polymorphisms in the VDR gene have been shown to nominally associate with ASD in multiple populations (Schmidt et al., 2015; Coskun et al., 2016; Bojovic et al., 2017; Cieslinska et al., 2017; Zhang et al., 2018). Serum levels of 25-hydroxyvitamin D were found to be significantly higher in ASD cases, and the FokI polymorphism was observed to have a significant effect on serum 25-hydroxyvitamin D levels in children with ASD, in Coskun et al., 2016. Whole blood VDR gene expression was found to be significantly higher in a cohort of 30 age and gender matched patients diagnosed with ASD compared to a cohort of 30 healthy controls (p < 0.0001) (Balta et al., 2018).

Molecular Function

Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells. Enters the nucleus upon vitamin D3 binding where it forms heterodimers with the retinoid X receptor/RXR. The VDR-RXR heterodimers bind to specific response elements on DNA and activate the transcription of vitamin D3-responsive target genes. Recruited to promoters via its interaction with BAZ1B/WSTF which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.

Reports related to VDR (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Schmidt RJ , et al. (2015) Yes -
2 Positive Association Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder. Cokun S , et al. (2016) Yes -
3 Positive Association Genetic predictors of celiac disease, lactose intolerance, and vitamin D function and presence of peptide morphins in urine of children with neurod... Bojovi K , et al. (2017) Yes -
4 Positive Association Vitamin D Receptor Gene Polymorphisms Associated with Childhood Autism. Cieliska A , et al. (2017) Yes -
5 Positive Association Polymorphisms in Vitamin D Receptor Genes in Association with Childhood Autism Spectrum Disorder. Zhang Z , et al. (2018) Yes -
6 Support Increased vitamin D receptor gene expression and rs11568820 and rs4516035 promoter polymorphisms in autistic disorder. Balta B , et al. (2018) Yes -
7 Negative Association No Association between Polymorphisms of Vitamin D and Oxytocin Receptor Genes and Autistic Spectrum Disorder in a Sample of Turkish Children. Bozdogan ST , et al. (2018) Yes -
8 Positive association Association between vitamin D receptor gene FokI and TaqI variants with autism spectrum disorder predisposition in Iranian population. Mobasheri L , et al. (2019) Yes -
9 Positive association The Correlation Between Vitamin D Receptor (VDR) Gene Polymorphisms and Autism: A Meta-analysis. Yang H and Wu X (2020) Yes -
10 Positive association Vitamin D Receptor Polymorphisms Associated with Autism Spectrum Disorder. Guerini FR , et al. (2020) Yes -
Rare Variants  

No rare variants reported.

Common Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1024+283G>A - intron_variant - - - 27155524 Cokun S , et al. (2016)
c.1025-49G>T;c.1175-49G>T - intron_variant - - - 31900887 Yang H and Wu X (2020)
c.1056T>C;c.1206T>C p.(=) synonymous_variant - - - 31900887 Yang H and Wu X (2020)
c.1056T>C;c.1206T>C p.(=) synonymous_variant - - - 27155524 Cokun S , et al. (2016)
c.1056T>C;c.1206T>C p.(=) synonymous_variant - - - 29581796 Zhang Z , et al. (2018)
c.1025-49G>T;c.1175-49G>T - intron_variant - - - 28891930 Cieliska A , et al. (2017)
c.1056T>C;c.1206T>C p.(=) synonymous_variant - - - 26073892 Schmidt RJ , et al. (2015)
c.1056T>C;c.1206T>C p.(=) synonymous_variant - - - 28891930 Cieliska A , et al. (2017)
c.1056T>C;c.1206T>C p.(=) synonymous_variant - - - 31589956 Mobasheri L , et al. (2019)
c.2T>C;c.152T>C p.Met1Thr;p.Met51Thr missense_variant - - - 27155524 Cokun S , et al. (2016)
c.2T>C;c.152T>C p.Met1Thr;p.Met51Thr missense_variant - - - 28738753 Bojovi K , et al. (2017)
c.2T>C;c.152T>C p.Met1Thr;p.Met51Thr missense_variant - - - 32083397 Guerini FR , et al. (2020)
SFARI Gene score
3

Suggestive Evidence

Polymorphisms in the VDR gene have been shown to nominally associate with ASD in multiple populations (Schmidt et al., 2015; Coskun et al., 2016; Bojovic et al., 2017; Cieslinska et al., 2017; Zhang et al., 2018). Serum levels of 25-hydroxyvitamin D were found to be significantly higher in ASD cases, and the FokI polymorphism was observed to have a significant effect on serum 25-hydroxyvitamin D levels in children with ASD, in Coskun et al., 2016. Whole blood VDR gene expression was found to be significantly higher in a cohort of 30 age and gender matched patients diagnosed with ASD compared to a cohort of 30 healthy controls (p < 0.0001) (Balta et al., 2018).

Score Delta: Score remained at 4

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.

1/1/2020
4
icon
4

Score remained at 4

Description

Polymorphisms in the VDR gene have been shown to nominally associate with ASD in multiple populations (Schmidt et al., 2015; Coskun et al., 2016; Bojovic et al., 2017; Cieslinska et al., 2017; Zhang et al., 2018). Serum levels of 25-hydroxyvitamin D were found to be significantly higher in ASD cases, and the FokI polymorphism was observed to have a significant effect on serum 25-hydroxyvitamin D levels in children with ASD, in Coskun et al., 2016. Whole blood VDR gene expression was found to be significantly higher in a cohort of 30 age and gender matched patients diagnosed with ASD compared to a cohort of 30 healthy controls (p < 0.0001) (Balta et al., 2018).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Polymorphisms in the VDR gene have been shown to nominally associate with ASD in multiple populations (Schmidt et al., 2015; Coskun et al., 2016; Bojovic et al., 2017; Cieslinska et al., 2017; Zhang et al., 2018). Serum levels of 25-hydroxyvitamin D were found to be significantly higher in ASD cases, and the FokI polymorphism was observed to have a significant effect on serum 25-hydroxyvitamin D levels in children with ASD, in Coskun et al., 2016. Whole blood VDR gene expression was found to be significantly higher in a cohort of 30 age and gender matched patients diagnosed with ASD compared to a cohort of 30 healthy controls (p < 0.0001) (Balta et al., 2018).

Reports Added
[New Scoring Scheme]
10/1/2018
icon
4

Increased from to 4

Description

Polymorphisms in the VDR gene have been shown to nominally associate with ASD in multiple populations (Schmidt et al., 2015; Coskun et al., 2016; Bojovic et al., 2017; Cieslinska et al., 2017; Zhang et al., 2018). Serum levels of 25-hydroxyvitamin D were found to be significantly higher in ASD cases, and the FokI polymorphism was observed to have a significant effect on serum 25-hydroxyvitamin D levels in children with ASD, in Coskun et al., 2016. Whole blood VDR gene expression was found to be significantly higher in a cohort of 30 age and gender matched patients diagnosed with ASD compared to a cohort of 30 healthy controls (p < 0.0001) (Balta et al., 2018).

Krishnan Probability Score

Score 0.43742139019163

Ranking 20212/25841 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.
ExAC Score

Score 0.39212521151842

Ranking 5999/18225 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
Sanders TADA Score

Score 0.9298307050994

Ranking 11269/18665 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).
Zhang D Score

Score -0.72257442956705

Ranking 20423/20870 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.
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