TY - JOUR
T1 - Convergent evidence linking neonatal vitamin D status and risk of neurodevelopmental disorders
T2 - a Danish case-cohort study
AU - Horsdal, Henriette Thisted
AU - Albiñana, Clara
AU - Zhu, Zhihong
AU - Boelt, Sanne Grundvad
AU - Borbye-Lorenzen, Nis
AU - Cohen, Arieh S
AU - Skogstrand, Kristin
AU - Melgaard, Lars
AU - MacSween, Nadia Jensen
AU - Thorbek, Marta Jadwiga
AU - Plana-Ripoll, Oleguer
AU - Petersen, Liselotte Vogdrup
AU - Bulik, Cynthia M
AU - Børglum, Anders D
AU - Mors, Ole
AU - Nordentoft, Merete
AU - Werge, Thomas
AU - Moen, Gunn-Helen
AU - D'Urso, Shannon
AU - Wray, Naomi R
AU - Vilhjálmsson, Bjarni J
AU - Agerbo, Esben
AU - Pedersen, Carsten Bøcker
AU - Mortensen, Preben Bo
AU - McGrath, John J
PY - 2025/6
Y1 - 2025/6
N2 - BACKGROUND: There is growing evidence linking neonatal vitamin D deficiency to an increased risk of schizophrenia, ADHD, and autism spectrum disorder (ASD). The aim of this study was to examine the association between two vitamin D biomarkers (25 hydroxyvitamin D [25(OH)D] and vitamin D-binding protein [DBP], and their related genetic correlates) and the risk of six mental disorders.METHODS: We used a population-based, case-cohort sample of all individuals born in Denmark between 1981 and 2005. Using Danish health registers with follow-up to Dec 31, 2012, we identified individuals diagnosed with major depressive disorder, bipolar disorder, schizophrenia, ADHD, ASD, and anorexia nervosa based on ICD-10 criteria. Additionally, a random subcohort from the general population was selected. Based on neonatal dried blood spots, we measured concentrations of 25(OH)D and DBP. Our primary analyses were based on hazard ratios (HR) with 95% CI and absolute risks for the six mental disorders according to measured concentrations of 25(OH)D and DBP. As secondary analyses, we examined the association between genetic predictors of 25(OH)D and DBP, and the six mental disorders, and Mendelian randomisation analyses based on published summary statistics for 25(OH)D, DBP, and the six mental disorders. People with lived experience contributed to the development of the guiding hypothesis.FINDINGS: We used the total population from the iPSYCH2012 design (n=88 764), which included individuals who developed the six mental disorders, major depressive disorder (n=24 240), bipolar disorder (n=1928), schizophrenia (n=3540), ADHD (n=18 726), ASD (n=16 146), anorexia nervosa (n=3643), and the randomly sampled subcohort (n=30 000). Among those who met a range of inclusion criteria (eg, measured 25[OH]D, DBP or genotype, and predominantly European ancestry), we measured 25(OH)D or DBP in 71 793 individuals (38 118 [53·1%] male and 33 675 [46·9%] female); 65 952 had 25(OH)D and 66 797 the DBP measurements. Significant inverse relationships were found between 25(OH)D and schizophrenia (HR 0·82, 95% CI 0·78-0·86), ASD (HR 0·93, 95% CI 0·90-0·96), and ADHD (HR 0·89, 95% CI 0·86-0·92). A significant inverse relationship was found between DBP and schizophrenia (HR 0·84, 95% CI 0·80-0·88). Based on polygenic risk scores, higher concentrations of 25(OH)D (adjusted for DBP) were significantly associated with a reduced risk of both ASD and schizophrenia. Analyses based on Mendelian randomisation provided support for a causal association between both lower 25(OH)D and DBP concentrations and an increased risk of ADHD.INTERPRETATION: Convergent evidence finds that neonatal vitamin D status is associated with an altered risk of mental disorders. Our study supports the hypothesis that optimising neonatal vitamin D status might reduce the incidence of a range of neurodevelopmental disorders.FUNDING: The Danish National Research Foundation.
AB - BACKGROUND: There is growing evidence linking neonatal vitamin D deficiency to an increased risk of schizophrenia, ADHD, and autism spectrum disorder (ASD). The aim of this study was to examine the association between two vitamin D biomarkers (25 hydroxyvitamin D [25(OH)D] and vitamin D-binding protein [DBP], and their related genetic correlates) and the risk of six mental disorders.METHODS: We used a population-based, case-cohort sample of all individuals born in Denmark between 1981 and 2005. Using Danish health registers with follow-up to Dec 31, 2012, we identified individuals diagnosed with major depressive disorder, bipolar disorder, schizophrenia, ADHD, ASD, and anorexia nervosa based on ICD-10 criteria. Additionally, a random subcohort from the general population was selected. Based on neonatal dried blood spots, we measured concentrations of 25(OH)D and DBP. Our primary analyses were based on hazard ratios (HR) with 95% CI and absolute risks for the six mental disorders according to measured concentrations of 25(OH)D and DBP. As secondary analyses, we examined the association between genetic predictors of 25(OH)D and DBP, and the six mental disorders, and Mendelian randomisation analyses based on published summary statistics for 25(OH)D, DBP, and the six mental disorders. People with lived experience contributed to the development of the guiding hypothesis.FINDINGS: We used the total population from the iPSYCH2012 design (n=88 764), which included individuals who developed the six mental disorders, major depressive disorder (n=24 240), bipolar disorder (n=1928), schizophrenia (n=3540), ADHD (n=18 726), ASD (n=16 146), anorexia nervosa (n=3643), and the randomly sampled subcohort (n=30 000). Among those who met a range of inclusion criteria (eg, measured 25[OH]D, DBP or genotype, and predominantly European ancestry), we measured 25(OH)D or DBP in 71 793 individuals (38 118 [53·1%] male and 33 675 [46·9%] female); 65 952 had 25(OH)D and 66 797 the DBP measurements. Significant inverse relationships were found between 25(OH)D and schizophrenia (HR 0·82, 95% CI 0·78-0·86), ASD (HR 0·93, 95% CI 0·90-0·96), and ADHD (HR 0·89, 95% CI 0·86-0·92). A significant inverse relationship was found between DBP and schizophrenia (HR 0·84, 95% CI 0·80-0·88). Based on polygenic risk scores, higher concentrations of 25(OH)D (adjusted for DBP) were significantly associated with a reduced risk of both ASD and schizophrenia. Analyses based on Mendelian randomisation provided support for a causal association between both lower 25(OH)D and DBP concentrations and an increased risk of ADHD.INTERPRETATION: Convergent evidence finds that neonatal vitamin D status is associated with an altered risk of mental disorders. Our study supports the hypothesis that optimising neonatal vitamin D status might reduce the incidence of a range of neurodevelopmental disorders.FUNDING: The Danish National Research Foundation.
KW - Humans
KW - Denmark/epidemiology
KW - Vitamin D/blood
KW - Female
KW - Male
KW - Infant, Newborn
KW - Vitamin D Deficiency/blood
KW - Vitamin D-Binding Protein/blood
KW - Mendelian Randomization Analysis
KW - Cohort Studies
KW - Neurodevelopmental Disorders/epidemiology
KW - Depressive Disorder, Major/epidemiology
KW - Risk Factors
KW - Schizophrenia/epidemiology
KW - Child
KW - Autism Spectrum Disorder/epidemiology
KW - Biomarkers/blood
KW - Case-Control Studies
KW - Adult
KW - Bipolar Disorder/epidemiology
KW - Adolescent
UR - http://www.scopus.com/inward/record.url?scp=105004921210&partnerID=8YFLogxK
U2 - 10.1016/S2215-0366(25)00099-9
DO - 10.1016/S2215-0366(25)00099-9
M3 - Journal article
C2 - 40379361
SN - 2215-0366
VL - 12
SP - 410
EP - 420
JO - The Lancet Psychiatry
JF - The Lancet Psychiatry
IS - 6
ER -