Serum Vitamin D Levels Demonstrates Causal Association with Psychiatric Disorders

by | Oct 20, 2023 | 2023, Brain Health, Vitamin D - Recommended Levels

Written by Chrystal Moulton, Staff Writer. Results demonstrate that ASD, schizophrenia, and bipolar disorder are potential independent risk factors for decreased 25OHD levels.

vitamin D capsulesVitamin D and calcium are essential to human health1. In psychiatric studies, higher concentrations of vitamin D was associated with the reduced risk of depression and psychotic-like symptoms2,3. Various other studies demonstrate that low vitamin D is associated with an increased risk of autism spectrum disorder4, Alzheimer’s disease5, and schizophrenia6. However, psychiatric research is not consistent regarding the association of serum vitamin and psychiatric disorders7,8. Research methods such as mendelian randomization and multivariable mendelian randomization have been established to draw causality in exposure and outcome associations while preventing reverse causality and controlling for potential confounders9,10. In the current trial, researchers used mendelian randomization method to assess association between calcium homeostasis markers (parathyroid hormone [PTH],  25-hydroxyvitamin D [25OHD], fibroblast growth factor-23 [FGF23], and calcium) and 9 psychiatric disorders11.

The study design was a bidirectional mendelian randomization and multivariate mendelian randomization analysis. Researchers used these methods to detect a causal relationship between genetically predicted calcium, PTH, FGF23, 25OHD and autism spectrum disease (ASD), bipolar disorder (BD), ADHD, Alzheimer’s disease (AD), anorexia nervosa (AN), obsessive-compulsive disorder (OCD), Tourette syndrome (TS), major depressive disorder (MDD), and schizophrenia (SCZ). Data was extracted from five genome wide associated studies. The validity of utilizing genetic single nucleotide polymorphisms (SNPs) for this design is based on 3 principles 12:

  1. Single nucleotide polymorphisms (SNPs) applied as instrumental variables (IVs) are related to exposures
  2. Instrumental variables cannot be associated with confounders
  3. Instrumental variables should not affect outcomes directly

Selection of single nucleotide polymorphisms (SNPs) for use as instrumental variables (IVs) in the mendelian randomization analysis required the SNPs to meet the threshold of P <0.00001. The inverse variance weighted method was used to calculate causal estimate while controlling heterogeneity of instrumental variables13. Multivariable mendelian randomization was used to verify direct causal relationships between psychiatric disorders and calcium homeostasis. Four additional tests were used to determine causality14. If one of these five methods produced significant results, then a causal relationship was considered to exist even after adjusting for multiple variables. The primary goal of this study was to use mendelian randomization and multivariable mendelian randomization analysis to investigate causal associations between calcium homeostasis markers (calcium, PTH, FGF23, 25OHD) and 9 psychiatric disorders (ASD, BD, SCZ, AN, MDD, OCD, ADHD, TS, AD).

Results from the inverse-variance weighted method showed that calcium was associated with lower odds of OCD (OR= 0.7891, P= 0.0337). Results from this method also predicted serum 25OHD levels were associated with lower odds of ASD (OR= 0.7520, P= 0.0223). Statistical analysis of 72 tests identified a causal link between schizophrenia and low serum 25OHD levels. To confirm the causal link between schizophrenia and serum 25OHD, researchers removed SNPs that were outliers and found the causal link between schizophrenia and low serum 25OHD levels that was maintained (P= 2.39 x 10 -7). Furthermore, the potential decrease in serum 25OHD levels was associated with causality in ASD and BD (P< 0.05). Multivariable mendelian randomization results showed that the causal association between 25OHD levels and schizophrenia was maintained even after adjusting for BMI, obesity, time spent outdoors, and mineral supplementation (P< 0.001). Bipolar disorder was also associated with 25OHD levels even after adjusting for BMI, time spent outdoors, and mineral supplementation (P< 0.05). Further analysis of ASD in relation to 25OHD levels following multivariable mendelian randomization showed the same results (P< 0.05). These results demonstrate that ASD, schizophrenia, and bipolar disorder are potential independent risk factors for decreased 25OHD levels. Multivariable mendelian randomization analysis for ADHD and calcium, ASD and FGF23, and OCD and calcium showed no significant causal relationships.

Results from this study indicated that schizophrenia, autism spectrum disorder, and bipolar disorder were potential risk factors for decreased serum 25 OHD levels. Furthermore, reverse mendelian randomization analysis indicated schizophrenia was significantly associated with decreased 25OHD levels. Additional studies will be needed to verify these results.

Source: Jiang, Miaomiao, Weiheng Yan, Xianjing Li, Liyang Zhao, Tianlan Lu, Dai Zhang, Jun Li, and Lifang Wang. “Calcium Homeostasis and Psychiatric Disorders: A Mendelian Randomization Study.” Nutrients 15, no. 18 (2023): 4051.

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Click here to read the full text study.

Posted October 19, 2023.

Chrystal Moulton BA, PMP, is a 2008 graduate of the University of Illinois at Chicago. She graduated with a bachelor’s in psychology with a focus on premedical studies and is a licensed project manager. She currently resides in Indianapolis, IN.

References:

  1. Gracia-Marco L. Calcium, Vitamin D, and Health. Nutrients. Feb 6 2020;12(2)doi:10.3390/nu12020416
  2. Mulugeta A, Lumsden A, Hyppönen E. Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study. Nutrients. Dec 30 2020;13(1)doi:10.3390/nu13010109
  3. Hedelin M, Löf M, Olsson M, et al. Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry. May 26 2010;10:38. doi:10.1186/1471-244x-10-38
  4. Wang T, Shan L, Du L, et al. Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry. Apr 2016;25(4):341-50. doi:10.1007/s00787-015-0786-1
  5. Afzal S, Bojesen SE, Nordestgaard BG. Reduced 25-hydroxyvitamin D and risk of Alzheimer’s disease and vascular dementia. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. May 2014;10(3):296-302. doi:10.1016/j.jalz.2013.05.1765
  6. Valipour G, Saneei P, Esmaillzadeh A. Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies. The Journal of clinical endocrinology and metabolism. Oct 2014;99(10):3863-72. doi:10.1210/jc.2014-1887
  7. Li B, Xu Y, Zhang X, et al. The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: a systematic review and meta-analysis of randomized controlled trials. Nutr Neurosci. Apr 2022;25(4):835-845. doi:10.1080/1028415x.2020.1815332
  8. Bränn E, Fransson E, White RA, et al. Inflammatory markers in women with postpartum depressive symptoms. J Neurosci Res. Jul 2020;98(7):1309-1321. doi:10.1002/jnr.24312
  9. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Statistics in medicine. Apr 15 2008;27(8):1133-63. doi:10.1002/sim.3034
  10. Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol. Jun 1 2019;48(3):713-727. doi:10.1093/ije/dyy262
  11. Jiang M, Yan W, Li X, et al. Calcium Homeostasis and Psychiatric Disorders: A Mendelian Randomization Study. Nutrients. Sep 19 2023;15(18)doi:10.3390/nu15184051
  12. Lawlor DA. Commentary: Two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol. Jun 2016;45(3):908-15. doi:10.1093/ije/dyw127
  13. Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Statistics in medicine. May 20 2016;35(11):1880-906. doi:10.1002/sim.6835
  14. Grant AJ, Burgess S. Pleiotropy robust methods for multivariable Mendelian randomization. Statistics in medicine. Nov 20 2021;40(26):5813-5830. doi:10.1002/sim.9156