Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study

Abstract

Background Vitamin D is essential for proper neurodevelopment and cognitive and behavioral function. We examined associations between autism spectrum disorder (ASD) and common, functional polymorphisms in vitamin D pathways. Methods Children aged 24–60 months enrolled from 2003 to 2009 in the population-based CHARGE case–control study were evaluated clinically and confirmed to have ASD (n = 474) or typical development (TD, n = 281). Maternal, paternal, and child DNA samples for 384 (81%) families of children with ASD and 234 (83%) families of TD children were genotyped for: TaqI, BsmI, FokI, and Cdx2 in the vitamin D receptor (VDR) gene, and CYP27B1 rs4646536, GC rs4588, and CYP2R1 rs10741657. Case–control logistic regression, family-based log-linear, and hybrid log-linear analyses were conducted to produce risk estimates and 95% confidence intervals (CI) for each allelic variant. Results Paternal VDR TaqI homozygous variant genotype was significantly associated with ASD in case–control analysis (odds ratio [OR] [CI]: 6.3 [1.9–20.7]) and there was a trend towards increased risk associated with VDR BsmI (OR [CI]: 4.7 [1.6–13.4]). Log-linear triad analyses detected parental imprinting, with greater effects of paternally-derived VDR alleles. Child GC AA-genotype/A-allele was associated with ASD in log-linear and ETDT analyses. A significant association between decreased ASD risk and child CYP2R1 AA-genotype was found in hybrid log-linear analysis. There were limitations of low statistical power for less common alleles due to missing paternal genotypes. Conclusions This study provides preliminary evidence that paternal and child vitamin D metabolism could play a role in the etiology of ASD; further research in larger study populations is warranted.

Lack of effect of vitamin D3supplementation in autism: a 20-week, placebo-controlled RCT

“…For example, paternal37 and individual38 39 vitamin D receptor (VDR) polymorphisms have been associated with increased ASD risk. We did not measure levels of vitamin D-binding protein, VDR or calcitriol (1,25D) which may have provided interesting insight here.…”

Maternal vitamin D deficiency and developmental origins of health and disease (DOHaD)

“…In an extensive epidemiological study, Childhood Autism Risks from Genetics and the Environment (CHARGE) showed an association between autism spectrum disorders (ASDs) and several functional polymorphisms in genes within the vitamin D pathway, including Bsm1, Taq1, Cdx2 and FokI in the vitamin D receptor (VDR) gene (Schmidt et al 2015). Importantly, this study pinpointed that the genotype AA/A-allele of GC rs4588, encoding the vitamin D-binding protein, was strongly associated with ASD in children (Schmidt et al 2015). Additionally, supplementation with high doses of vitamin D (ranging from 300 IU/kg/day to 5000 IU/day) in two open-label trials has been found to improve clinical core symptoms of autism in ~75% of affected children (Cannell 2017).…”

Vitamin D Deficiency During Pregnancy and Autism Spectrum Disorders Development

“…Multiple studies have reported inadequate VD status in children with ASD. Reduced intake and decreased exposure to UVB radiation have been considered as potential causes, but abnormal VD activity due to genetic polymorphisms of the genes encoding for the enzymes that hydroxylate VD 3 or in the gene that encodes VDR was found to be the most common reason (73)(74)(75). A 2016 meta-analysis of 11 studies, including 870 ASD children and 782 typically developing children, demonstrated signifi cantly lower serum 25(OH)D 3 concentrations in ASD cases than in controls (12).…”