Gestational vitamin D deficiency and autism-related traits: the Generation R Study

A A E Vinkhuyzen, D W Eyles, T H J Burne, L M E Blanken, C J Kruithof, F Verhulst, V W Jaddoe, H Tiemeier, J J McGrath, A A E Vinkhuyzen, D W Eyles, T H J Burne, L M E Blanken, C J Kruithof, F Verhulst, V W Jaddoe, H Tiemeier, J J McGrath

Abstract

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l-1. Compared with the 25OHD sufficient group (25OHD>50 nmol l-1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, β=0.06, P<0.001; cord blood n=1712, β=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. APA APA. Diagnostic and statistical manual of mental disorders: DSM-5 5th edn, American Psychiatric Association: Washington, DC, USA, 2013.
    1. Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res 2009; 204: 313–321.
    1. Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry 2004; 61: 618–627.
    1. Kolevzon A, Gross R, Reichenberg A. Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 2007; 161: 326–333.
    1. Lyall K, Schmidt RJ, Hertz-Picciotto I. Maternal lifestyle and environmental risk factors for autism spectrum disorders. Int J Epidemiol 2014; 43: 443–464.
    1. Mazahery H, Camargo CA, Conlon C, Beck KL, Kruger MC, von Hurst PR. Vitamin D and autism spectrum disorder: a literature review. Nutrients 2016; 8: 236.
    1. Cannell JJ. Autism and vitamin D. Med Hypotheses 2008; 70: 750–759.
    1. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266–281.
    1. Groves NJ, McGrath JJ, Burne THJ. Vitamin D as a neurosteroid affecting the developing and adult brain. Annu Rev Nutr 2014; 34: 117–141.
    1. McGrath JJ, Burne TH, Féron F, Mackay-Sim A, Eyles DW. Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophr Bull 2010; 36: 1073–1078.
    1. Deluca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. The role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol 2013; 39: 458–484.
    1. Kocovska E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil 2012; 33: 1541–1550.
    1. McGrath JJ, Burne TH, Feron F, Mackay-Sim A, Eyles DW. Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophr Bull 2010; 36: 1073–1078.
    1. Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J 2014; 28: 2398–2413.
    1. Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Kusel MM, Hart PH. Maternal serum vitamin D levels during pregnancy and offspring neurocognitive development. Pediatrics 2012; 129: 485–493.
    1. Morales E, Guxens M, Llop S, Rodriguez-Bernal CL, Tardon A, Riano I et al. Circulating 25-hydroxyvitamin D3 in pregnancy and infant neuropsychological development. Pediatrics 2012; 130: e913–e920.
    1. Hanieh S, Ha TT, Simpson JA, Thuy TT, Khuong NC, Thoang DD et al. Maternal vitamin D status and infant outcomes in rural Vietnam: a prospective cohort study. PLoS One 2014; 9: e99005.
    1. Keim SA, Bodnar LM, Klebanoff MA. Maternal and cord blood 25(OH)-vitamin D concentrations in relation to child development and behaviour. Paediatr Perinat Epidemiol 2014; 28: 434–444.
    1. Tylavsky FA, Kocak M, Murphy LE, Graff JC, Palmer FB, Volgyi E et al. Gestational vitamin 25(OH)D status as a risk factor for receptive language development: a 24-month, longitudinal, observational study. Nutrients 2015; 7: 9918–9930.
    1. Whitehouse AJ, Holt BJ, Serralha M, Holt PG, Hart PH, Kusel MM. Maternal vitamin D levels and the autism phenotype among offspring. J Autism Dev Disord 2013; 43: 1495–1504.
    1. Wang T, Shan L, Du L, Feng J, Xu Z, Staal WG et al. Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2016; 25: 341–350.
    1. Fernell E, Bejerot S, Westerlund J, Miniscalco C, Simila H, Eyles D et al. Autism spectrum disorder and low vitamin D at birth: a sibling control study. Mol Autism 2015; 6: 3.
    1. Wing L. The continuum of autistic characteristics. Diagnosis and assessment in autism. Springer US, New York, USA, 1988, pp 91–110.
    1. Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord 2001; 31: 5–17.
    1. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry 2010; 167: 1349–1356.
    1. Robinson EB, Koenen KC, McCormick MC, Munir K, Hallett V, Happe F et al. Evidence that autistic traits show the same etiology in the general population and at the quantitative extremes (5%, 2.5%, and 1%). Arch Gen Psychiatry 2011; 68: 1113–1121.
    1. Ronald A, Hoekstra RA. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet 2011; 156B: 255–274.
    1. Robinson EB St, Pourcain B, Anttila V, Kosmicki JA, Bulik-Sullivan B, Grove J et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat Genet 2016; 48: 552–555.
    1. Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL et al. Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord 2003; 33: 427–433.
    1. Vinkhuyzen AA, Eyles DW, Burne TH, Blanken LM, Kruithof CJ, Verhulst F et al. Prevalence and predictors of vitamin D deficiency based on maternal mid-gestation and neonatal cord bloods: The Generation R Study. J Steroid Biochem Mol Biol 2015; 164: 161–167.
    1. Jaddoe VW, van Duijn CM, Franco OH, van der Heijden AJ, van Iizendoorn MH, de Jongste JC et al. The Generation R Study: design and cohort update 2012. Eur J Epidemiol 2012 27: 739–756.
    1. Kruithof CJ, Kooijman MN, van Duijn CM, Franco OH, de Jongste JC, Klaver CC et al. The Generation R Study: biobank update 2015. Eur J Epidemiol 2014; 29: 911–927.
    1. Statistiek CBvdImmigrants in the Netherlands 2004. Voorburg: The Netherlands, 2004.
    1. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. In: A Catharine Ross, Christine LT, Ann LY, Heather B Del Valle (eds). Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press: Washington DC, USA, 2010.
    1. Eyles D, Anderson C, Ko P, Jones A, Thomas A, Burne T et al. A sensitive LC/MS/MS assay of 250H vitamin D-3 and 250H vitamin D-2 in dried blood spots. Clin Chim Acta 2009; 403: 145–151.
    1. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911–1930.
    1. Hillman LS, Haddad JG. Human perinatal vitamin D metabolism. I. 25-Hydroxyvitamin D in maternal and cord blood. J Pediatr 1974; 84: 742–749.
    1. Salle BL, Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH. Perinatal metabolism of vitamin D. Am J Clin Nutr 2000; 71: 1317S–1324S.
    1. Jacquemyn Y, Ajaji M, Karepouan N. Vitamin D levels in maternal serum and umbilical cord blood in a multi-ethnic population in Antwerp, Belgium. Facts Views Vis Obgyn 2013; 5: 3–5.
    1. Vieth Streym S, Kristine Moller U, Rejnmark L, Heickendorff L, Mosekilde L, Vestergaard P. Maternal and infant vitamin D status during the first 9 months of infant life-a cohort study. Eur J Clin Nutr 2013; 67: 1022–1028.
    1. Karras SN, Shah I, Petroczi A, Goulis DG, Bili H, Papadopoulou F et al. An observational study reveals that neonatal vitamin D is primarily determined by maternal contributions: implications of a new assay on the roles of vitamin D forms. Nutr J 2013; 12: 77.
    1. Wigham S, McConachie H, Tandos J, Le Couteur AS. Gateshead Millennium Study core team. The reliability and validity of the Social Responsiveness Scale in a UK general child population. Res Dev Disabil 2012; 33: 944–950.
    1. Roman GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VW, Hofman A, de Rijke YB et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 2013; 74: 733–742.
    1. Blanken LM, Mous SE, Ghassabian A, Muetzel RL, Schoemaker NK, El Marroun H et al. Cortical morphology in 6- to 10-year old children with autistic traits: a population-based neuroimaging study. Am J Psychiatry 2015; 172: 479–486.
    1. Yudell M, Roberts D, DeSalle R, Tishkoff S. Taking race out of human genetics. Science 2016; 351: 564–565.
    1. Medina-Gomez C, Felix JF, Estrada K, Peters MJ, Herrera L, Kruithof CJ et al. Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the Generation R Study. Eur J Epidemiol 2015; 30: 317–330.
    1. Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB et al. Variance component model to account for sample structure in genome-wide association studies. Nat Genet 2010; 42: 348–354.
    1. Jaddoe VW, Bakker R, van Duijn CM, van der Heijden AJ, Lindemans J, Mackenbach JP et al. The Generation R Study Biobank: a resource for epidemiological studies in children and their parents. Eur J Epidemiol 2007; 22: 917–923.
    1. Newgard CD, Lewis RJ. Accounting for missing data in clinical research—reply. JAMA 2016; 315: 518.
    1. Schafer J. Estimation/multiple imputation for mixed categorical and continuous data. 1.0-9 edn, 2015.
    1. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the Vitamin D receptor and 1alpha-hydroxylase in human brain. J Chem Neuroanat 2005; 29: 21–30.
    1. Cui X, Gooch H, Groves NJ, Sah P, Burne TH, Eyles DW et al. Vitamin D and the brain: key questions for future research. J Steroid Biochem Mol Biol 2015; 148: 305–309.
    1. McGrath JJ, Eyles DW, Pedersen CB, Anderson C, Ko P, Burne TH et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry 2010; 67: 889–894.
    1. Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45: 984–994.
    1. Latimer CS, Brewer LD, Searcy JL, Chen KC, Popovic J, Kraner SD et al. Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci USA 2014; 111: E4359–E4366.
    1. Cui X, Gooch H, Groves NJ, Sah P, Burne TH, Eyles DW et al. Vitamin D and the brain: key questions for future research. J Steroid Biochem Mol Biol 2015; 148: 305–309.
    1. Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM et al. CACNA1C (Ca(v)1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol 2012; 99: 1–14.
    1. Casamassima F, Hay AC, Benedetti A, Lattanzi L, Cassano GB, Perlis RH. L-type calcium channels and psychiatric disorders: a brief review. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1373–1390.
    1. Eyles DW, Burne THJ, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol 2013; 34: 47–64.
    1. Kaneko I, Sabir MS, Dussik CM, Whitfield GK, Karrys A, Hsieh JC et al. 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. FASEB J 2015; 29: 4023–4035.
    1. Groves NJ, Kesby JP, Eyles DW, McGrath JJ, Mackay-Sim A, Burne TH. Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav Brain Res 2012; 241C: 120–131.
    1. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 2002; 52: 805–810.
    1. Blatt GJ, Fatemi SH. Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications. Anat Rec (Hoboken) 2011; 294: 1646–1652.
    1. Atladottir HO, Schendel DE, Henriksen TB, Hjort L, Parner ET. Gestational age and autism spectrum disorder: trends in risk over time. Autism Res 2016; 9: 224–231.
    1. Morales E, Julvez J, Torrent M, Ballester F, Rodriguez-Bernal CL, Andiarena A et al. Vitamin D in pregnancy and attention deficit hyperactivity disorder-like symptoms in childhood. Epidemiology 2015; 26: 458–465.
    1. Hus V, Bishop S, Gotham K, Huerta M, Lord C. Factors influencing scores on the social responsiveness scale. J Child Psychol Psychiatry 2013; 54: 216–224.
    1. Hanratty J, Livingstone N, Robalino S, Terwee CB, Glod M, Oono IP et al. Systematic review of the measurement properties of tools used to measure behaviour problems in young children with autism. PLoS One 2015; 10: e0144649.
    1. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag 2008; 4: 827–836.
    1. Hansen KE, Johnson RE, Chambers KR, Johnson MG, Lemon CC, Vo TN et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical tTrial. JAMA Intern Med 2015; 175: 1612–1621.
    1. Di Daniele N, Carbonelli MG, Candeloro N, Iacopino L, De Lorenzo A, Andreoli A. Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri- and post-menopause women; a double-blind, randomized, controlled trial. Pharmacol Res 2004; 50: 637–641.
    1. van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA et al. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry 2016; 21: 585.

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