Timing of birth and risk of multiple sclerosis: population based study
http://www.100md.com
《英国医生杂志》
1 Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA, 2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, 3 Department of Medical Genetics and Faculty of Medicine (Division of Neurology), University of British Columbia, Vancouver, BC, Canada V6T 2B5, 4 Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford, OX2 6HE, 5 Dalhousie University, Halifax, NS, Canada B3H 4R2
Correspondence to: G C Ebers george.ebers@clneuro.ox.ac.uk
Abstract
Classic studies of twins, adoptees, half siblings, and families1-4 have led to a widely accepted notion that multiple sclerosis (MS) is a complex trait in which susceptibility is determined by the interplay of genes and environmental factors. Environment seems to influence risk at a population level, but specific details remain unclear. The most striking clue to the role of environment has always been the gradient with latitude, which is most obvious in Australia, where the risk in temperate Tasmania is fivefold that in subtropical Queensland5 6 but where ethnic origins are relatively uniform. The gradient is also seen in several other countries, including New Zealand7 and the United States.8 The role of environment is seen in twin studies, which report a 70-90% discordance in identical twins.1 Studies of migrants indicate that risk for MS is strongly associated with place of residence early in life,6 9 but it is not easy to retrospectively study gestational, perinatal, and childhood periods in adult onset diseases. In Canada, the risk for a dizygotic twin of someone with MS is almost twice that for a full non-twin sibling.1 This may implicate environmental factor(s) such as shared timing of gestation or birth, or both. Furthermore, the study of half siblings has shown a maternal effect that could be environmental in nature.5
Studies of month of birth and risk of MS have been carried out in several cohorts of people with MS, but sample sizes, ethnic groups, and statistical methods differed for each study and findings have been inconsistent.10-14 Although significant differences in month of birth compared with population based controls have been reported, they have not been for the same months.
Methods
Among Canadian patients with MS 8.5% fewer than expected were born in November compared with other months and slightly but not significantly more were born in May. This finding was replicated in British patients with MS, where the numbers born in both months were significantly different from controls. A pooled analysis including results from previously published Danish10 and Swedish11 studies confirmed the May peak and November nadir. This overall dataset of patients with MS born in the northern hemisphere showed a 13% increase in risk of MS for those born in May compared with November (95% confidence interval 5% to 22%).
We used unaffected siblings from the Canadian collaborative project15 as a second control group, eliminating potential confounding by ethnic differences in seasonal birth patterns or by survival being influenced by month of birth. The unaffected sibling controls confirmed and extended the findings as they also differed from population controls in a direction opposite to that of their affected siblings. This may be viewed as internal confirmation of the effect of month of birth on risk.
The results were derived from more than 42 000 patients with MS from northern countries, where MS has a high prevalence. Canada, Denmark,10 Great Britain, and Sweden11 each have large databases and distinct seasons, and nearly all cases of MS in Canada are identified.15
We have conclusively shown the association between month of birth and risk of MS in northern countries. The sample size, internal replications, and selection of appropriate controls indicate that this is unlikely to be an artefact. Our pooled data show that being born in May is associated with increased risk, and the Canadian and British datasets clearly show that people born in November have the lowest risk. Correlation of specific years of increased risk related to season with features such as ultraviolet radiation, temperature, or weather patterns may help to elucidate this effect further.
Month of birth and risk of MS has been examined in other populations. The Danish study found that more people with MS had been born in March, April, May, and June, and a Swedish study showed an association with March, May, and July.11 When these data were combined, more people with MS had been born in the five consecutive months from March to July,2 although the Swedish study did not directly confirm the Danish findings. Smaller studies in cohorts from Sicily,13 the Netherlands, Japan, and Hungary14 were not consistent, but a study from Vancouver showed the same degree of effect in a smaller sample size.12 Relatively small sample sizes may not have sufficient power to disentangle meaningful seasonal influences.14-17 None of these studies can be considered as definitive.
Although the birth month results in MS now seem clear, the interpretation is not. May and November show significance in the pooled analysis and the peaks of altered risk are exactly six months apart. Although the reduced risk for November seems to exist also for December births in some datasets, the changes in risk are remarkably discrete. The abrupt change in risk by month suggests a threshold effect for both increased and decreased risk, something that is not easily explained. These observed changes may partly explain the increased risk of MS in second generation Asian and Caribbean migrants to the United Kingdom—that is, moving to the United Kingdom does not changes their genes but something in the climate may do so.18
Possible explanations of association
The risk factor(s) responsible for the effect of timing of birth must vary seasonally and probably interacts with development of the central nervous system or immune systems, or both. Among candidate factors are maternal folate,19 correlates of infant birth weight and virus infection, and factors also implicated in the effect of season of birth on schizophrenia.17 Undoubtedly other cyclic interactions remain to be identified.
Previous findings of associations between higher latitudes and risk of MS (Sardinians and Sami being notable exceptions) have suggested that exposure to the sun may account for the geographical variation of MS.20 Most biologically active vitamin D is generated in the skin with exposure to ultraviolet radiation21 and an increased risk of MS related to month of birth could reflect well documented seasonal deficiency in maternal concentrations of vitamin D.22 Vitamin D treatment reduces severity of symptoms and progression in experimental autoimmune encephalomyelitis (EAE), which is a mouse model of MS.23 Furthermore, exposure to sun during childhood is associated with a reduced risk of multiple sclerosis,24 and this may also extend to timing of birth. If the excess of MS in those born in May is related to maternal vitamin D deficiency, studies on blood concentrations suggest that the end of the second or the third trimester are the crucial time points.22 Vitamin D receptors are present in the brain, and gestational vitamin D deficiency has striking effects on brain development in experimental animals.25
What is already known on this topic
Susceptibility to multiple sclerosis (MS) is influenced by genetic and environmental factors
An association with latitude in early life has been shown in migrants from regions of differing risk
A maternal parent of origin effect shown in half siblings with MS from Canada suggested that environment acts in gestation or the neonatal period to determine risk for this adult onset disease
What this study adds
In northern countries the risk of MS is greater for people born in May and lower for those born in November
This effect is greater in Scotland, where the population prevalence of this disease is highest
These findings support suggestions from studies in twins and half siblings that the gestational or neonatal environment, or both, influence the risk of MS later in life
The observed May/November birth ratio in living incident cases from Scotland (1.89), Denmark (1.22),10 Sweden (1.18),11 and Canada (1.13) decreases in order of population prevalence (fig 2). This suggests that the seasonal birth effect may be connected with environmental factors determining prevalence rates. These are powerful, seem to act at a broad population level,1-3 and may hold the key to disease prevention. The "parent of origin" effect, recently reported in MS,5 may suggest that, at least in part, environmental factors are maternally mediated and influence development in the nervous or immune system, or both.
We thank Irene Yee, Maria Criscuoli, Randy Holmes, Kevin Atkins, and Don Templer (at Alliant International University) for their help with this study and James Gowans, Rodney Phillips, Anne Spurkland, Pierre Duquette, Ed Burton, Stacey Cherny, Iain Chalmers, and Michael Boehnke for help with the manuscript. We also thank the participants of the vitamin D workshop held in Toronto in April 2002 for valuable insight, discussion, and advice and Nina Jablonski and George Chaplin for sharing their expertise. The Canadian Collaborative Study Group includes D W Paty, S A Hashimoto, V Devonshire, J Hooge, J Oger, L Kastrukoff, and T Traboulsee (Vancouver); L Metz (Calgary); S Warren (Edmonton); W Hader (Saskatoon); R Nelson and M Freedman (Ottawa); D Brunet (Kingston); J Paulseth (Hamilton); G Rice and M Kremenchutzky (London); P O'Connor, T Gray, and M Hohol (Toronto); P Duquette and Y Lapierre (Montreal); J-P Bouchard (Quebec City); V Bhan and C Maxner (Halifax); and W Pryse-Phillips and M Stefanelli (St Johns).
Contributors: GCE (guarantor) conceived the Canadian national network of MS clinics and its role in this study. ADS and GCE conceived this investigation and are the principal investigators of the Canadian collaborative study. GCE and ADS supervised the data collection and research. CJW and DAD did the primary analyses for the Canadian dataset, and PMR conceived the study and completed analyses of the UK dataset. CJW wrote the first draft, with subsequent revision from all authors. TJM provided a helpful suggestion for future research.
Funding: This work was part of a larger project funded by the MS Society of Canada Scientific Research Foundation. CJW and DAD were supported bystudentships from the MS Society of Canada, during the time this study was mainly completed. ADS is a Michael Smith Distinguished Scholar.
Competing interests: None declared.
Ethical approval: The study was approved by the University of Western Ontario and the University of British Columbia, which were the two main sites of data collection. Each Canadian MS clinic obtained ethical approval from their local review board.
References
Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003;100: 12877-82.
Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995;377: 150-1.
Ebers G, Sadovnick A, Dyment D, Yee I, Willer C, Risch N, et al. A parent of origin effect in multiple sclerosis: observations in half siblings. Lancet 2004;363: 847-50.
Ebers GC, Yee IM, Sadovnick AD, Duquette P. Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol 2000;48: 927-31.
McLeod JG, Hammond SR, Hallpike JF. Epidemiology of multiple sclerosis in Australia. With NSW and SA survey results. Med J Aust 1994;160: 117-22.
Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000;123: 968-74.
Fawcett J, Skegg DCG. Geographic distribution of MS in New Zealand: evidence from hospital admissions and deaths. Neurology 1988;38: 416-8.
Templer DI, Trent NH, Spencer DA, Trent A, Corgiat MD, Mortensen PB, et al. Season of birth in multiple sclerosis. Acta Neurol Scand 1992;85: 107-9.
Wiberg M, Templer DI. Season of birth in multiple sclerosis in Sweden: replication of Denmark findings. J Orthomol Med 1994;9: 71-74.
Kurtzke JF, Beebe GW, Norman JE Jr. Epidemiology of multiple sclerosis in US veterans: 1. race, sex, and geographic distribution. Neurology 1979;29: 1228-35.
Dean G. Annual incidence, prevalence, and mortality of multiple sclerosis in white South-African-born and in white immigrants to South Africa. BMJ 1967;ii: 724-30.
Sadovnick AD, Yee IM. Season of birth in multiple sclerosis. Acta Neurol Scand 1994;89: 190-1.
Salemi G, Ragonese P, Aridon P, Reggio A, Nicoletti A, Buffa D, et al. Is season of birth associated with multiple sclerosis? Acta Neurol Scand 2000;101: 381-3.
Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonal birth patterns of neurological disorders. Neuroepidemiology 2000;19: 177-85.
Sadovnick AD, Risch NJ, Ebers GC. Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method. Canadian Collaborative Study Group. Can J Neurol Sci 1998;25: 216-21.
Rothwell PM, Charlton D. High incidence and prevalence of multiple sclerosis in south east Scotland: evidence of a genetic predisposition. J Neurol Neurosurg Psychiatry 1998;64: 730-5.
Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 1997;28: 1-38.
Elian M, Dean G. Multiple sclerosis among the United Kingdom-born children of immigrants from the West Indies. J Neurol Neurosurg Psychiatry 1987;50: 327-32.
Branda RF, Eaton JW. Skin color and nutrient photolysis: an evolutionary hypothesis. Science 1978;201: 625-6.
Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation and other variables. Acta Psychiat (Scand) 1960;35(suppl 147): 132.
Holick MF, Smith E, Pincus S. Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis. Arch Dermatol 1987;123: 1677-83a.
Vieth R, Cole DE, Hawker GA, Trang HM, Rubin LA. Wintertime vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it. Eur J Clin Nutr 2001;55: 1901-7.
Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A 1996;93: 7861-4.
Van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ 2003;327: 316.
McGrath JJ, Feron FP, Burne TH, Mackay-Sim A, Eyles DW. Vitamin D3-implications for brain development. J Steroid Biochem Mol Biol 2004;89-90: 557-60.(Cristen J Willer, postdoctoral fellow1, )
Correspondence to: G C Ebers george.ebers@clneuro.ox.ac.uk
Abstract
Classic studies of twins, adoptees, half siblings, and families1-4 have led to a widely accepted notion that multiple sclerosis (MS) is a complex trait in which susceptibility is determined by the interplay of genes and environmental factors. Environment seems to influence risk at a population level, but specific details remain unclear. The most striking clue to the role of environment has always been the gradient with latitude, which is most obvious in Australia, where the risk in temperate Tasmania is fivefold that in subtropical Queensland5 6 but where ethnic origins are relatively uniform. The gradient is also seen in several other countries, including New Zealand7 and the United States.8 The role of environment is seen in twin studies, which report a 70-90% discordance in identical twins.1 Studies of migrants indicate that risk for MS is strongly associated with place of residence early in life,6 9 but it is not easy to retrospectively study gestational, perinatal, and childhood periods in adult onset diseases. In Canada, the risk for a dizygotic twin of someone with MS is almost twice that for a full non-twin sibling.1 This may implicate environmental factor(s) such as shared timing of gestation or birth, or both. Furthermore, the study of half siblings has shown a maternal effect that could be environmental in nature.5
Studies of month of birth and risk of MS have been carried out in several cohorts of people with MS, but sample sizes, ethnic groups, and statistical methods differed for each study and findings have been inconsistent.10-14 Although significant differences in month of birth compared with population based controls have been reported, they have not been for the same months.
Methods
Among Canadian patients with MS 8.5% fewer than expected were born in November compared with other months and slightly but not significantly more were born in May. This finding was replicated in British patients with MS, where the numbers born in both months were significantly different from controls. A pooled analysis including results from previously published Danish10 and Swedish11 studies confirmed the May peak and November nadir. This overall dataset of patients with MS born in the northern hemisphere showed a 13% increase in risk of MS for those born in May compared with November (95% confidence interval 5% to 22%).
We used unaffected siblings from the Canadian collaborative project15 as a second control group, eliminating potential confounding by ethnic differences in seasonal birth patterns or by survival being influenced by month of birth. The unaffected sibling controls confirmed and extended the findings as they also differed from population controls in a direction opposite to that of their affected siblings. This may be viewed as internal confirmation of the effect of month of birth on risk.
The results were derived from more than 42 000 patients with MS from northern countries, where MS has a high prevalence. Canada, Denmark,10 Great Britain, and Sweden11 each have large databases and distinct seasons, and nearly all cases of MS in Canada are identified.15
We have conclusively shown the association between month of birth and risk of MS in northern countries. The sample size, internal replications, and selection of appropriate controls indicate that this is unlikely to be an artefact. Our pooled data show that being born in May is associated with increased risk, and the Canadian and British datasets clearly show that people born in November have the lowest risk. Correlation of specific years of increased risk related to season with features such as ultraviolet radiation, temperature, or weather patterns may help to elucidate this effect further.
Month of birth and risk of MS has been examined in other populations. The Danish study found that more people with MS had been born in March, April, May, and June, and a Swedish study showed an association with March, May, and July.11 When these data were combined, more people with MS had been born in the five consecutive months from March to July,2 although the Swedish study did not directly confirm the Danish findings. Smaller studies in cohorts from Sicily,13 the Netherlands, Japan, and Hungary14 were not consistent, but a study from Vancouver showed the same degree of effect in a smaller sample size.12 Relatively small sample sizes may not have sufficient power to disentangle meaningful seasonal influences.14-17 None of these studies can be considered as definitive.
Although the birth month results in MS now seem clear, the interpretation is not. May and November show significance in the pooled analysis and the peaks of altered risk are exactly six months apart. Although the reduced risk for November seems to exist also for December births in some datasets, the changes in risk are remarkably discrete. The abrupt change in risk by month suggests a threshold effect for both increased and decreased risk, something that is not easily explained. These observed changes may partly explain the increased risk of MS in second generation Asian and Caribbean migrants to the United Kingdom—that is, moving to the United Kingdom does not changes their genes but something in the climate may do so.18
Possible explanations of association
The risk factor(s) responsible for the effect of timing of birth must vary seasonally and probably interacts with development of the central nervous system or immune systems, or both. Among candidate factors are maternal folate,19 correlates of infant birth weight and virus infection, and factors also implicated in the effect of season of birth on schizophrenia.17 Undoubtedly other cyclic interactions remain to be identified.
Previous findings of associations between higher latitudes and risk of MS (Sardinians and Sami being notable exceptions) have suggested that exposure to the sun may account for the geographical variation of MS.20 Most biologically active vitamin D is generated in the skin with exposure to ultraviolet radiation21 and an increased risk of MS related to month of birth could reflect well documented seasonal deficiency in maternal concentrations of vitamin D.22 Vitamin D treatment reduces severity of symptoms and progression in experimental autoimmune encephalomyelitis (EAE), which is a mouse model of MS.23 Furthermore, exposure to sun during childhood is associated with a reduced risk of multiple sclerosis,24 and this may also extend to timing of birth. If the excess of MS in those born in May is related to maternal vitamin D deficiency, studies on blood concentrations suggest that the end of the second or the third trimester are the crucial time points.22 Vitamin D receptors are present in the brain, and gestational vitamin D deficiency has striking effects on brain development in experimental animals.25
What is already known on this topic
Susceptibility to multiple sclerosis (MS) is influenced by genetic and environmental factors
An association with latitude in early life has been shown in migrants from regions of differing risk
A maternal parent of origin effect shown in half siblings with MS from Canada suggested that environment acts in gestation or the neonatal period to determine risk for this adult onset disease
What this study adds
In northern countries the risk of MS is greater for people born in May and lower for those born in November
This effect is greater in Scotland, where the population prevalence of this disease is highest
These findings support suggestions from studies in twins and half siblings that the gestational or neonatal environment, or both, influence the risk of MS later in life
The observed May/November birth ratio in living incident cases from Scotland (1.89), Denmark (1.22),10 Sweden (1.18),11 and Canada (1.13) decreases in order of population prevalence (fig 2). This suggests that the seasonal birth effect may be connected with environmental factors determining prevalence rates. These are powerful, seem to act at a broad population level,1-3 and may hold the key to disease prevention. The "parent of origin" effect, recently reported in MS,5 may suggest that, at least in part, environmental factors are maternally mediated and influence development in the nervous or immune system, or both.
We thank Irene Yee, Maria Criscuoli, Randy Holmes, Kevin Atkins, and Don Templer (at Alliant International University) for their help with this study and James Gowans, Rodney Phillips, Anne Spurkland, Pierre Duquette, Ed Burton, Stacey Cherny, Iain Chalmers, and Michael Boehnke for help with the manuscript. We also thank the participants of the vitamin D workshop held in Toronto in April 2002 for valuable insight, discussion, and advice and Nina Jablonski and George Chaplin for sharing their expertise. The Canadian Collaborative Study Group includes D W Paty, S A Hashimoto, V Devonshire, J Hooge, J Oger, L Kastrukoff, and T Traboulsee (Vancouver); L Metz (Calgary); S Warren (Edmonton); W Hader (Saskatoon); R Nelson and M Freedman (Ottawa); D Brunet (Kingston); J Paulseth (Hamilton); G Rice and M Kremenchutzky (London); P O'Connor, T Gray, and M Hohol (Toronto); P Duquette and Y Lapierre (Montreal); J-P Bouchard (Quebec City); V Bhan and C Maxner (Halifax); and W Pryse-Phillips and M Stefanelli (St Johns).
Contributors: GCE (guarantor) conceived the Canadian national network of MS clinics and its role in this study. ADS and GCE conceived this investigation and are the principal investigators of the Canadian collaborative study. GCE and ADS supervised the data collection and research. CJW and DAD did the primary analyses for the Canadian dataset, and PMR conceived the study and completed analyses of the UK dataset. CJW wrote the first draft, with subsequent revision from all authors. TJM provided a helpful suggestion for future research.
Funding: This work was part of a larger project funded by the MS Society of Canada Scientific Research Foundation. CJW and DAD were supported bystudentships from the MS Society of Canada, during the time this study was mainly completed. ADS is a Michael Smith Distinguished Scholar.
Competing interests: None declared.
Ethical approval: The study was approved by the University of Western Ontario and the University of British Columbia, which were the two main sites of data collection. Each Canadian MS clinic obtained ethical approval from their local review board.
References
Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003;100: 12877-82.
Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995;377: 150-1.
Ebers G, Sadovnick A, Dyment D, Yee I, Willer C, Risch N, et al. A parent of origin effect in multiple sclerosis: observations in half siblings. Lancet 2004;363: 847-50.
Ebers GC, Yee IM, Sadovnick AD, Duquette P. Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol 2000;48: 927-31.
McLeod JG, Hammond SR, Hallpike JF. Epidemiology of multiple sclerosis in Australia. With NSW and SA survey results. Med J Aust 1994;160: 117-22.
Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000;123: 968-74.
Fawcett J, Skegg DCG. Geographic distribution of MS in New Zealand: evidence from hospital admissions and deaths. Neurology 1988;38: 416-8.
Templer DI, Trent NH, Spencer DA, Trent A, Corgiat MD, Mortensen PB, et al. Season of birth in multiple sclerosis. Acta Neurol Scand 1992;85: 107-9.
Wiberg M, Templer DI. Season of birth in multiple sclerosis in Sweden: replication of Denmark findings. J Orthomol Med 1994;9: 71-74.
Kurtzke JF, Beebe GW, Norman JE Jr. Epidemiology of multiple sclerosis in US veterans: 1. race, sex, and geographic distribution. Neurology 1979;29: 1228-35.
Dean G. Annual incidence, prevalence, and mortality of multiple sclerosis in white South-African-born and in white immigrants to South Africa. BMJ 1967;ii: 724-30.
Sadovnick AD, Yee IM. Season of birth in multiple sclerosis. Acta Neurol Scand 1994;89: 190-1.
Salemi G, Ragonese P, Aridon P, Reggio A, Nicoletti A, Buffa D, et al. Is season of birth associated with multiple sclerosis? Acta Neurol Scand 2000;101: 381-3.
Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonal birth patterns of neurological disorders. Neuroepidemiology 2000;19: 177-85.
Sadovnick AD, Risch NJ, Ebers GC. Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method. Canadian Collaborative Study Group. Can J Neurol Sci 1998;25: 216-21.
Rothwell PM, Charlton D. High incidence and prevalence of multiple sclerosis in south east Scotland: evidence of a genetic predisposition. J Neurol Neurosurg Psychiatry 1998;64: 730-5.
Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 1997;28: 1-38.
Elian M, Dean G. Multiple sclerosis among the United Kingdom-born children of immigrants from the West Indies. J Neurol Neurosurg Psychiatry 1987;50: 327-32.
Branda RF, Eaton JW. Skin color and nutrient photolysis: an evolutionary hypothesis. Science 1978;201: 625-6.
Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation and other variables. Acta Psychiat (Scand) 1960;35(suppl 147): 132.
Holick MF, Smith E, Pincus S. Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis. Arch Dermatol 1987;123: 1677-83a.
Vieth R, Cole DE, Hawker GA, Trang HM, Rubin LA. Wintertime vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it. Eur J Clin Nutr 2001;55: 1901-7.
Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A 1996;93: 7861-4.
Van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, et al. Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. BMJ 2003;327: 316.
McGrath JJ, Feron FP, Burne TH, Mackay-Sim A, Eyles DW. Vitamin D3-implications for brain development. J Steroid Biochem Mol Biol 2004;89-90: 557-60.(Cristen J Willer, postdoctoral fellow1, )