Abstract
Background/Objectives:
Observational studies have suggested low serum levels of vitamin B12 or folate to be risk factors of depression and anxiety. However, these results may be biased by confounding and reverse causation. Mendelian randomization studies are not subject to these limitations. The aim was to examine the association of genetic scores of vitamin B12 and folate-associated alleles with depression and anxiety.
Subjects/Methods:
The study included 4126 participants from two Danish population-based studies. Serum vitamin B12 and folate were measured. Weighed allele scores were calculated as the sum of weights (genetic effect sizes) for 12 and two variants increasing circulating levels of vitamin B12 and folate, respectively. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety.
Results:
An increased weighed allele score for serum vitamin B12 was associated with decreased odds of a SCL-90-R score above the 90th percentile (OR 0.540 (95%CI 0.302–0.967)) in Health2006 but not in Inter99, in the pooled analysis (OR 0.817 (95%CI 0.331–2.018)) or with other outcomes. The weighed allele score for serum folate was not associated with any of the measured outcome variables: SCL-90-R scores of depression (pooled OR 0.603 (95%CI 0.101–3.602)), anxiety (pooled OR 0.619 (95%CI 0.110–3.495)), combined score or history of doctor-diagnosed depression or anxiety.
Conclusion:
Our results do not provide evidence for a causal effect of circulating folate or vitamin B12 on the risk of depression or anxiety. However, we cannot rule out small to moderate effects, and thus large scale studies are needed.
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References
Kessler RC, Aguilar-Gaxiola S, Alonso J, Chatterji S, Lee S, Ormel J et al. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiologia e psichiatria sociale 2009; 18: 23–33.
Lopez AD, Murray CC . The global burden of disease, 1990-2020. Nature medicine 1998; 4: 1241–1243.
Prince M, Patel V, Saxena S, Maj M, Maselko J, Phillips MR et al. No health without mental health. Lancet 2007; 370: 859–877.
Wahlbeck K, Westman J, Nordentoft M, Gissler M, Laursen TM . Outcomes of Nordic mental health systems: life expectancy of patients with mental disorders. The British journal of psychiatry: the journal of mental science 2011; 199: 453–458.
Brown TA, Barlow DH . Dimensional versus categorical classification of mental disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders and beyond: comment on the special section. Journal of abnormal psychology 2005; 114: 551–556.
Olsen LR, Mortensen EL, Bech P . The SCL-90 and SCL-90 R versions validated by item response models in a Danish community sample. Acta psychiatrica Scandinavica 2004; 110: 225–229.
Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. The American journal of psychiatry 2000; 157: 1552–1562.
Beesdo K, Pine DS, Lieb R, Wittchen HU . Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Archives of general psychiatry 2010; 67: 47–57.
Husemoen LL, Ebstrup JF, Mortensen EL, Schwarz P, Skaaby T, Thuesen BH et al. Serum 25-hydroxyvitamin D and self-reported mental health status in adult Danes. European journal of clinical nutrition 2016; 70: 78–84.
Bottiglieri T . Homocysteine and folate metabolism in depression. Progress in neuro-psychopharmacology & biological psychiatry 2005; 29: 1103–1112.
Kumar N . Neurologic aspects of cobalamin (B12) deficiency. Handbook of clinical neurology 2014; 120: 915–926.
De-Regil LM, Pena-Rosas JP, Fernandez-Gaxiola AC, Rayco-Solon P . Effects and safety of periconceptional oral folate supplementation for preventing birth defects. The Cochrane database of systematic reviews 2015; (12): Cd007950.
Gilbody S, Lightfoot T, Sheldon T . Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. Journal of epidemiology and community health 2007; 61: 631–637.
Seppala J, Koponen H, Kautiainen H, Eriksson JG, Kampman O, Leiviska J et al. Association between vitamin b12 levels and melancholic depressive symptoms: a Finnish population-based study. BMC psychiatry 2013; 13: 145.
Biemans E, Hart HE, Rutten GE, Cuellar Renteria VG, Kooijman-Buiting AM, Beulens JW . Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. Acta diabetologica 2015; 52: 383–393.
Moorthy D, Peter I, Scott TM, Parnell LD, Lai CQ, Crott JW et al. Status of vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. The Journal of nutrition 2012; 142: 1554–1560.
Okereke OI, Cook NR, Albert CM, Van Denburgh M, Buring JE, Manson JE . Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women. The British journal of psychiatry: the journal of mental science 2015; 206: 324–331.
Beydoun MA, Shroff MR, Beydoun HA, Zonderman AB . Serum folate, vitamin B-12, and homocysteine and their association with depressive symptoms among U.S. adults. Psychosomatic medicine 2010; 72: 862–873.
Almeida OP, Ford AH, Flicker L . Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. International psychogeriatrics / IPA 2015; 27: 727–737.
Burgess S, Thompson SG . Use of allele scores as instrumental variables for Mendelian randomization. International journal of epidemiology 2013; 42: 1134–1144.
Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V et al. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS genetics 2013; 9: e1003530.
Smith GD, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? International journal of epidemiology 2003; 32: 1–22.
Gilbody S, Lewis S, Lightfoot T . Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. American journal of epidemiology 2007; 165: 1–13.
Halsted CH, Wong DH, Peerson JM, Warden CH, Refsum H, Smith AD et al. Relations of glutamate carboxypeptidase II (GCPII) polymorphisms to folate and homocysteine concentrations and to scores of cognition, anxiety, and depression in a homogeneous Norwegian population: the Hordaland Homocysteine Study. The American journal of clinical nutrition 2007; 86: 514–521.
Jamerson BD, Payne ME, Garrett ME, Ashley-Koch AE, Speer MC, Steffens DC . Folate metabolism genes, dietary folate and response to antidepressant medications in late-life depression. International journal of geriatric psychiatry 2013; 28: 925–932.
Thuesen BH, Cerqueira C, Aadahl M, Ebstrup JF, Toft U, Thyssen JP et al. Cohort Profile: the Health2006 cohort, research centre for prevention and health. International journal of epidemiology 2014; 43: 568–575.
Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C . A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. European journal of cardiovascular prevention and rehabilitation: official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 2003; 10: 377–386.
Jorgensen T, Ladelund S, Borch-Johnsen K, Pisinger C, Schrader AM, Thomsen T et al. Screening for risk of cardiovascular disease is not associated with mental distress: the Inter99 study. Preventive medicine 2009; 48: 242–246.
Derogatis LR . SCL-90-R: Symptom Checklist-90-R. Administration, scoring and procedures manual, 3rd edn. National Computer Systems: Minneapolis, Minnesota, 1994.
Derogatis LR, Cleary PA . Factorial invariance across gender for the primary symptom dimensions of the SCL-90. The British journal of social and clinical psychology 1977; 16: 347–356.
Olsen LR, Mortensen EL, Bech P, Symptom Checklist (SCL-90, SCL-90-R og SCL-92), In: Elsass P, Ivanouw J, Mortensen EL, Poulsen S, Rosenbaum B (eds) Håndbog for psykologer og psykiatere. Psykologisk Forlag A/S: Copenhagen, 2006.
Husemoen LL, Skaaby T, Thuesen BH, Grarup N, Sandholt CH, Hansen T et al. Mendelian randomisation study of the associations of vitamin B12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three Danish population-based studies. European journal of clinical nutrition 2016; 70: 613–619.
Toft U, Kristoffersen L, Ladelund S, Bysted A, Jakobsen J, Lau C et al. Relative validity of a food frequency questionnaire used in the Inter99 study. European journal of clinical nutrition 2008; 62: 1038–1046.
Saltin B, Grimby G . Physiological analysis of middle-aged and old former athletes. Comparison with still active athletes of the same ages. Circulation 1968; 38: 1104–1115.
Rosengren A, Wilhelmsen L . Physical activity protects against coronary death and deaths from all causes in middle-aged men. Evidence from a 20-year follow-up of the primary prevention study in Goteborg. Annals of epidemiology 1997; 7: 69–75.
Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM . Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Archives of general psychiatry 2003; 60: 618–626.
Forti P, Rietti E, Pisacane N, Olivelli V, Dalmonte E, Mecocci P et al. Blood homocysteine and risk of depression in the elderly. Archives of gerontology and geriatrics 2010; 51: 21–25.
VanderWeele TJ, Tchetgen Tchetgen EJ, Cornelis M, Kraft P . Methodological challenges in mendelian randomization. Epidemiology (Cambridge, Mass.) 2014; 25: 427–435.
Moulton CD, Pickup JC, Ismail K . The link between depression and diabetes: the search for shared mechanisms. The lancet. Diabetes & endocrinology 2015; 3: 461–471.
Hardt J, Gerbershagen HU, Franke P . The symptom check-list, SCL-90-R: its use and characteristics in chronic pain patients. European journal of pain (London, England) 2000; 4: 137–148.
Davey Smith G, Hemani G . Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Human molecular genetics 2014; 23: R89–R98.
Acknowledgements
The study was supported by Aase and Ejnar Danielsen’s Foundation. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen and is partly funded by an unrestricted donation from the Novo Nordisk Foundation.
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Møllehave, L., Skaaby, T., Simonsen, K. et al. Association studies of genetic scores of serum vitamin B12 and folate levels with symptoms of depression and anxiety in two danish population studies. Eur J Clin Nutr 71, 1054–1060 (2017). https://doi.org/10.1038/ejcn.2017.97
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DOI: https://doi.org/10.1038/ejcn.2017.97
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