Next generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis etc.). We review current next generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic aetiology of complex neurological diseases, with specific focus on multiple sclerosis. We highlight particular pitfalls in next generation sequencing experiments and speculate on both clinical and research applications of these sequencing platforms for complex neurological disorders in the future.
Next generation sequencing; transcriptomics; functional genomics; complex disease; neurological disease
Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased risk of SAH.
We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999–2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts.
There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison’s disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn’s disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison’s disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura (RR = 2.42, 1.86-3.11), primary biliary cirrhosis (RR = 2.21, 1.43-3.16) and SLE (RR = 3.76, 3.08-4.55).
Our findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted.
The cause of sporadic amyotrophic lateral sclerosis (SALS) remains unknown. We attempted to find out if occupational exposure to toxicants plays a part in the pathogenesis of this disease. In an Australia-wide case-control study we compared the lifetime occupations of 611 SALS and 775 control individuals. Occupations were coded using country-specific as well as international classifications. The risk of SALS for each occupation was calculated with odds ratios using logistic regression. In addition, the literature was searched for possible toxicant links between our findings and previously-reported occupational associations with SALS. Male occupations in our study that required lower skills and tasks tended to have increased risks of SALS, and conversely, those occupations that required higher skills and tasks had decreased risks of SALS. Of all the occupations, only truck drivers, where exposure to diesel exhaust is common, maintained an increased risk of SALS throughout all occupational groups. Another large case-control study has also found truck drivers to be at risk of SALS, and almost two-thirds of occupations, as well as military duties, that have previously been associated with SALS have potential exposure to diesel exhaust. In conclusion, two of the largest case-control studies of SALS have now found that truck drivers have an increased risk of SALS. Since exposure to diesel exhaust is common in truck drivers, as well as in other occupations that have been linked to SALS, exposure to this toxicant may underlie some of the occupations that are associated with SALS.
Mercury is a neurotoxicant linked with psychiatric symptoms at high levels of exposure. However, it is unclear whether an association is present at the low exposure levels in the US adult population.
Materials and Methods
Cross-sectional associations of total blood mercury and depression were assessed in 6,911 adults age ≥20 in the National Health and Nutrition Examination Survey (NHANES), 2005–2008. The Patient Health Questionnaire-9 was used to assess depression (high likelihood of a depressive spectrum disorder diagnosis; score 5–27).
Unadjusted survey weighted logistic regression suggested that higher total blood mercury was associated with lower odds of depression (Odds Ratio = 0.49, 95% Confidence Interval: 0.36–0.65, comparing the highest and lowest mercury quintiles). This association largely disappeared after adjustment for sociodemographic variables (income-poverty ratio, education, marital status). However, in age-stratified analyses, this inverse relationship remained in older adults (age ≥40) even after adjustment for sociodemographic variables. Simulation analyses adjusting for expected confounding effects of fish intake suggested that the inverse relationship among older adults may be plausibly attributed to residual confounding (Odds Ratio = 0.75, 95% Confidence Interval: 0.50–1.12, comparing the highest and lowest mercury quintiles).
Higher total blood mercury was not associated with increased odds of depression. The lower odds of depression in older adults with higher total blood mercury may be due to residual confounding.
Genome-wide analysis of vitamin D receptor (VDR) binding sites in THP-1 human monocyte-like cells highlighted the interleukin 8 gene, also known as chemokine CXC motif ligand 8 (CXCL8). CXCL8 is a chemotactic cytokine with important functions during acute inflammation as well as in the context of various cancers. The nine genes of the CXCL cluster and the strong VDR binding site close to the CXCL8 gene are insulated from neighboring genes by CCCTC-binding factor (CTCF) binding sites. Only CXCL8, CXCL6 and CXCL1 are expressed in THP-1 cells, but all three are up-regulated primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes. Formaldehyde-assisted isolation of regulatory elements sequencing analysis of the whole CXCL cluster demonstrated 1,25(OH)2D3-dependent chromatin opening exclusively for the VDR binding site. In differentiated THP-1 cells the CXCL8 gene showed a 33-fold higher basal expression, but is together with CXCL6 and CXCL1 still a primary 1,25(OH)2D3 target under the control of the same genomic VDR binding site. In summary, both in undifferentiated and differentiated THP-1 cells the genes CXCL8, CXCL6 and CXCL1 are under the primary control of 1,25(OH)2D3 and its receptor VDR. Our observation provides further evidence for the immune-related functions of vitamin D.
To re-analyse bicycle overtaking data collected by Walker (2007) with a view to assess factors associated with close passing (<1 m), to adjust for other observed factors in a multivariable analysis, and to assess the extent to which the sample size in the original analysis may have contributed to spurious results.
A re-analysis of 2,355 motor vehicle passing events recorded by Walker that includes information on cyclist's distance to the kerb, vehicle size and colour, city of observation, time of day, whether the event occurred while in a bikelane and helmet wearing. Each variable was considered for a final, multivariable model using purposeful selection of variables. The analysis was repeated using multiple logistic regression with passing distance dichotomised by the one metre rule. Bootstrap p-values were computed using sample sizes computed from conventional values of power and effect size.
The previously observed significant association between passing distance and helmet wearing was not found when dichotomised by the one metre rule. Other factors were found to be significantly associated with close passing including cyclists' distance to the kerb, vehicle size and city of observation (Salisbury or Bristol, UK). P-values from bootstrap samples indicate the significance of helmet wearing resulted from an overly large sample size.
After re-analysis of Walker's data, helmet wearing is not associated with close motor vehicle passing. The results, however, highlight other more important factors that may inform effective bicycle safety strategies.
Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.
We analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts.
After hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema.
This study shows that patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases, although we cannot rule out reverse causality or confounding. Further study of these associations is warranted and these data may aid further public health studies.
Vitamin D; Immune disease; Hospital episode statistics
Previous meta-analyses have had conflicting conclusions regarding the differences between laparoscopic and open techniques in patients with Crohn’s Disease. The objective of this meta-analysis was to compare outcomes in patients with Crohn’s disease undergoing laparoscopic or open surgical resection.
A literature search of EMBASE, MEDLINE, The Cochrane Central Register of Controlled Trials and the US National Institute of Health’s Clinical Trials Registry was completed. Randomized clinical trials and non-randomized comparative studies were included if laparoscopic and open surgical resections were compared. Primary outcomes assessed included perioperative complications, recurrence requiring surgery, small bowel obstruction and incisional hernia.
34 studies were included in the analysis, and represented 2,519 patients. Pooled analysis showed reduced perioperative complications in patients undergoing laparoscopic resection vs. open resection (Risk Ratio 0.71, 95% CI 0.58 – 0.86, P = 0.001). There was no evidence of a difference in the rate of surgical recurrence (Rate Ratio 0.78, 95% CI 0.54 – 1.11, P = 0.17) or small bowel obstruction (Rate Ratio 0.63, 95% CI 0.28 – 1.45, P = 0.28) between techniques. There was evidence of a decrease in incisional hernia following laparoscopic surgery (Rate Ratio 0.24, 95% CI 0.07 – 0.82, P = 0.02).
This is the largest review in this topic. The results of this analysis are based primarily on non-randomized studies and thus have significant limitations in regards to selection bias, confounding, lack of blinding and potential publication bias. Although we found evidence of decreased perioperative complications and incisional hernia in the laparoscopic group, further randomized controlled trials, with adequate follow up, are needed before strong recommendations can be made.
Laparoscopy; Crohn’s disease; Perioperative complications; Surgical recurrence; Hernia; Small bowel obstruction
Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1−/− B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.
Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB).
We analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts.
In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison’s disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture’s syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)).
These two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.
Hospital episode statistics; Immune disease; Tuberculosis
Genome-wide association studies (GWAS), although efficient to detect genes involved in complex diseases, are not designed to measure the real effect of the genes. This is illustrated here by the example of IL2RA in multiple sclerosis (MS). Association between IL2RA and MS is clearly established, although the functional variation is still unknown: the effect of IL2RA might be better described by several SNPs than by a single one. This study investigates whether a pair of SNPs better explains the observed linkage and association data than a single SNP. In total, 522 trio families and 244 affected sib-pairs were typed for 26 IL2RA SNPs. For each SNP and pairs of SNPs, the phased genotypes of patients and controls were compared to determine the SNP set offering the best risk discrimination. Consistency between the genotype risks provided by the retained set and the identical by descent allele sharing in affected sib-pairs was assessed. After controlling for multiple testing, the set of SNPs rs2256774 and rs3118470, provides the best discrimination between the case and control genotype distributions (P-corrected=0.009). The relative risk between the least and most at-risk genotypes is 3.54 with a 95% confidence interval of [2.14–5.94]. Furthermore, the linkage information provided by the allele sharing between affected sibs is consistent with the retained set (P=0.80) but rejects the SNP reported in the literature (P=0.006). Establishing a valid modeling of a disease gene is essential to test its potential interaction with other genes and to reconstruct the pathophysiological pathways.
modeling; multiple SNP analysis; affected sib-pair; IL2RA; multiple sclerosis
Weekend admissions have been shown to be associated with an increased risk of mortality compared with weekday admissions for many diagnoses. We analysed emergency department admissions within the Scottish National Health Service to investigate whether mortality is increased in case of weekend emergency department admissions.
A cohort study.
Scotland National Health Service (NHS) emergency departments.
5 271 327 emergency department admissions between 1999 and 2009. We included all patients admitted via emergency departments recorded in the Scottish Morbidity Records (SMR01) in NHS, Scotland for whom complete demographic data were available.
Primary outcome measures
Death as recorded by the General Register Office (GRO).
There was a significantly increased probability of death associated with a weekend emergency admission compared with admission on a weekday (unadjusted OR 1.27, 95% CI 1.26 to 1.28, p<0.0001; adjusted for year of admission, gender, age, deprivation quintile and number of comorbidities OR 1.42, 95% CI 1.40 to 1.43, p<0.0001).
Despite a general reduction in mortality over the last 11 years, there is still a significant excess mortality associated with weekend emergency admissions. Further research should be undertaken to identify the precise mechanisms underlying this effect so that measures can be put in place to reduce patient mortality.
Accident & Emergency Medicine
Patients with multiple sclerosis (MS) have been reported to be at higher risk of fracture than other people. We sought to test this hypothesis in a large database of hospital admissions in England.
We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999–2010). Rate ratios for fractures were determined, comparing fracture rates in a cohort of all people in England admitted with MS and rates in a comparison cohort.
Significantly elevated risk for all fractures was found in patients with MS (rate ratio (RR) = 1.99, 95% confidence interval (CI) = 1.93-2.05)). Risks were particularly high for femoral fractures (femoral neck fracture RR = 2.79 (2.65-2.93); femoral shaft fracture RR 6.69 (6.12-7.29)), and fractures of the tibia or ankle RR = 2.81 (2.66-2.96).
Patients with MS have an increased risk of fractures. Caregivers should aim to optimize bone health in MS patients.
Multiple sclerosis; Fractures; Epidemiology
Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS.
Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.
Studies investigating a proposed association between multiple sclerosis (MS) and migraine have produced conflicting results and a great range in the prevalence rate of migraine in MS patients. By meta-analysing all available data we aimed to establish an overall estimate of any association in order to more accurately inform clinicians and care-givers about a potential association between MS and migraine.
Pubmed and EMBASE were searched to identify suitable studies. Studies were included if they were a case-control study or cohort study in which controls were not reported to have another neurological condition, were available in English, and specified migraine as a headache sub-type. The odds ratio (OR) of migraine in MS patients vs. controls was calculated using the inverse variance with random effects model in Review Manager 5.1.
Eight studies were selected for inclusion, yielding a total of 1864 MS patients and 261563 control subjects. We found a significant association between migraine and MS (OR = 2.60, 95% CI 1.12–6.04), although there was significant heterogeneity. Sensitivity analysis showed that migraine without aura was associated with MS OR = 2.29 (95% CI 1.14–4.58), with no significant heterogeneity.
MS patients are more than twice as likely to report migraine as controls. Care providers should be alerted to ask MS patients about migraine in order to treat it and potentially improve quality of life. Future work should further investigate the temporal relationship of this association and relationship to the clinical characteristics of MS.
Genetic-epidemiological studies on monozygotic (MZ) twins have been used for decades to tease out the relative contributions of genes and the environment to a trait. Phenotypic discordance in MZ twins has traditionally been ascribed to non-shared environmental factors acting after birth, however recent data indicate that this explanation is far too simple. In this paper, we review other reasons for discordance, including differences in the in utero environment, genetic mosaicism, and stochastic factors, focusing particularly on epigenetic discordance. Epigenetic differences are gaining increasing recognition. Although it is clear that in specific cases epigenetic alterations provide a causal factor in disease etiology, the overall significance of epigenetics in twin discordance remains unclear. It is also challenging to determine the causality and relative contributions of environmental, genetic, and stochastic factors to epigenetic variability. Epigenomic profiling studies have recently shed more light on the dynamics of temporal methylation change and methylome heritability, yet have not given a definite answer regarding their relevance to disease, because of limitations in establishing causality. Here, we explore the subject of epigenetics as another component in human phenotypic variability and its links to disease focusing particularly on evidence from MZ twin studies.
Twins; Discordance; Epigenetics; Heritability; Environment
More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis.
Multiple sclerosis (MS) has a remarkable geographic distribution inversely paralleling that of regional ultraviolet radiation, supporting the hypothesis that vitamin D plays a central role in the disease etiology. The major histocompatibility complex exerts the largest genetic contribution to MS susceptibility, but much risk remains unexplained and direct gene-environment interaction is a strong candidate for this additional risk. Such interactions may hold the key for disease prevention.
Several recent studies strengthen the candidacy of vitamin D as a key player in the causal cascade to MS. This includes a newly identified gene-environment interaction between vitamin D and the main MS-linked HLA-DRB1*1501 allele and evidence showing that vitamin D levels are significantly lower in patients with MS as compared to controls. Also, a recent study in twins with MS supports the notion that vitamin D levels are under regulation by genetic variation in the 1α-hydroxylase and vitamin D receptor genes, perhaps pointing to their importance in the disease pathogenesis.
These findings have important practical implications for studies of disease mechanisms and prevention. Missing genetic risk may partly be explained by gene-environment interactions. More practically important is that these observations highlight a pressing need to determine if vitamin D supplementation can reduce the risk of multiple sclerosis (MS). However, the timing of action and the tissues in which this interaction takes place are not clear and future studies in prospective cohorts and animal models will be essential for deciphering the role of vitamin D in MS.
= major histocompatibility complex;
= multiple sclerosis;
= vitamin D receptor;
= vitamin D response element.
A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case–Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values ≤0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648–0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716–0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS.
multiple sclerosis (MS); polymorphisms; genetics; H6PD gene; 1p36.22; association
Our aim was to investigate whether there is a season-of-birth effect in
anorexia nervosa. In a meta-analysis, we compared the distribution of anorexia
births (n = 1293) from four independent UK cohorts to that of the general UK
population (n = 21 914 037), using both the Walter & Elwood seasonality
and chi-squared tests. We found an excess of anorexia births from March to
June (odds ratio (OR) = 1.15, 95% CI 1.03–1.29, P = 0.012) and a deficit
from September to October (OR = 0.8, 95% CI 0.68–0.94, P = 0.007). These
results indicate that environmental risk factor(s) are operative during
gestation or immediately after birth and their identification will be
important for disease prevention strategies.
We review here our current understanding of the genetic aetiology of the common complex neurological disease multiple sclerosis (MS). The strongest genetic risk factor for MS is the major histocompatibility complex which was identified in the 1970s. In 2011, after a number of genome-wide association studies have been completed and have identified approximately 20 new genes for MS, we ask the question—what is next for the genetics of MS?
Multiple sclerosis (MS) is a neurological disorder with a highly characteristic disease distribution. Prevalence and incidence in general increase with increasing distance from the equator. Similarly the female to male sex ratio increases with increasing latitude. Multiple possible risk factors have been hypothesised for this epidemiological trend, including human leukocyte antigen allele frequencies, ultraviolet exposure and subsequent vitamin D levels, smoking and Epstein-Barr virus. In this study we undertook a study of medical records across Scotland on an NHS health board level of resolution to examine the epidemiology of MS in this region.
Methods and Results
We calculated the number and rate of patient-linked hospital admissions throughout Scotland between 1997 and 2009 from the Scottish Morbidity Records. We used weighted-regression to examine correlations between these measures of MS, and latitude and smoking prevalence. We found a highly significant relationship between MS patient-linked admissions and latitude (r weighted by standard error (rsw) = 0.75, p = 0.002). There was no significant relationship between smoking prevalence and MS patient-linked admissions.
There is a definite latitudinal effect on MS risk across Scotland, arising primarily from an excess of female MS patients at more Northerly latitudes. Whether this is a true gradient or whether a threshold effect may apply at particular latitude will be revealed only by further research. A number of genetic and environmental factors may underlie this effect.