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We review the practical application of the tools for studying the genetic epidemiology of complex disease. Whole-genome association studies highlight the need to understand the genetic epidemiology. Elucidating the genetic basis of disease anticipated from these studies has been incomplete, and the importance of the environment and its potential interaction with genes cannot be overlooked. Multiple sclerosis yields several key lessons including how epistatic effects might overshadow the small effects of genes identified from whole-genome association studies. We reinterpret twin studies and demonstrate the use and advantages of adoptee, half-sibling and avuncular-pair studies. These show that the environment acts at a population level, strongly indicating epigenetic modifications to germline susceptibility. There is good reason to think that such interactions will be within the major histocompatibility complex, in which strong epistatic effects have already been demonstrated. Family-based data in multiple sclerosis are applicable to other neurological traits.
The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 x 10(-10)). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.
Hereditary spastic paraplegia (HSP) comprises a group of inherited neurodegenerative disorders with the shared characteristics of progressive weakness and spasticity predominantly affecting the lower limbs. Limited pathological accounts have described a 'dying back' axonal degeneration in this disease. However, the distribution and extent of axonal loss has not been elucidated in a quantitative way. We have studied post-mortem material from six HSP patients and 32 controls in detail. The population of axons was examined quantitatively in the corticospinal tracts from the medulla to the lumbar spinal cord and the sensory tracts from the lumbar to upper cervical spinal cord. Myelin and axon-stained sections were employed to estimate the notional area and axonal density, respectively, of both tracts. Our results indicate that in the corticospinal tracts there is a significant reduction in area and axonal density at all levels investigated in HSP compared to controls. In the corticospinal tracts, the ratio of medulla and lumbar total axonal number was significantly greater in HSP cases compared to controls suggesting more pronounced axonal loss in the distal neuraxis in HSP than in controls. The sensory tracts in HSP, in contrast, showed a significant reduction in area and axonal density only in the upper regions of the spinal cord. Similar to the corticospinal tracts, the ratio of lumbar and upper cervical cord total axonal number in the sensory tracts was increased in HSP cases compared to controls. These findings are consistent with a length-dependent 'dying back' axonopathy. Nerve fibre loss was not size-selective with both small and large diameter fibres affected. In HSP, axonal loss is widespread and symmetrical and its extent tract-specific. The characterization of the nature of axonal loss in HSP, where this is a primary phenomenon, may help the interpretation of axonal loss in conditions such as multiple sclerosis where the sequence of events is less clear.
Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group.
From a population-based sample of 15,504 patients attending Canadian multiple sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings. Twenty-three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17% (95% CI of 0.10%-0.24%). Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population. Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins. However, this correction may not be appropriate in this special case. Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS. Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is genetically determined. Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease.
Multiple sclerosis (MS) is now thought to be a complex trait determined by genetic and non-genetic (environmental) factors. The study group, identified from the Canadian Collaborative Project on Genetic Susceptibility to MS, consisted of 1,083 MS index cases, 2,166 of their parents and 3,112 of their sibs. The results, together with those of a previous study on an independent data set, suggest that gender, age of MS onset and having one parent with MS may individually and interactively alter sib risks for MS. These data are important for genetic counselling and for molecular genetic (genome screens, candidate gene analyses) studies.
Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene.
The hyperkalemic periodic paralyses are a clinically heterogeneous group of autosomal dominant syndromes characterized by episodic paralysis associated with an elevated serum potassium level. Affected individuals in the same family tend to have homogeneous symptom complexes, although phenotypic variation is present among different families. For example, myotonia is absent in some pedigrees, present in others, and, in a third variant, paramyotonia congenita, myotonia coexists with cold-induced paralysis. Electrophysiological studies have demonstrated variant-specific abnormalities in skeletal muscle membrane sodium conductance. We tested the hypothesis that hyperkalemic periodic paralysis (without myotonia) and paramyotonia congenita are tightly linked to the tetrodotoxin-sensitive adult skeletal muscle sodium channel gene on chromosome 17q23-25 in two large pedigrees. The DNA polymorphisms detected in the growth hormone skeletal muscle sodium channel complex (GH1-SCN4A) and by flanking polymorphic markers (D17S74 and D17S40) demonstrated no recombinants between the disease phenotypes and this complex. Phenotypic variation in the hereditary hyperkalemic periodic paralyses may result from allelic heterogeneity at the tetrodotoxin-sensitive adult skeletal muscle sodium channel locus.
The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course.
Controversy exists regarding the predictive value of the early clinical course of multiple sclerosis (MS). Three parameters often considered are the attack rate, the first interattack interval and the rate at which disability develops in the early years of the disease. We have recorded the time to reach successive levels of disability defined by the Kurtzke Disability Status Scale (DSS) in 1,099 MS patients followed at University Hospital, London, Canada between 1972 and 1984. Our population is particularly suitable because of its size, the high degree of ascertainment of cases in the community, and the regular follow-up provided. Life table analysis was used to compare survival in patients stratified according to the above three parameters using DSS 6 as end point. Significant differences were evident in the survival distributions. Despite the extensive interindividual variation in the rate at which disability developed, the early course of MS may be useful in determining the relative risk of rapid progression.
To determine the prevalence and nature of pain in multiple sclerosis, we evaluated by questionnaire, interview, and chart review 159 patients residing in Middlesex County and followed in the MS Clinic at University Hospital, London, Ontario, Canada. Eighty-eight patients (55%) had either an acute or chronic pain syndrome at some time during their disease. Fifteen patients (9%) with acute pain syndromes had episodes of paroxysmal tic-like pain diagnosed in seven as trigeminal neuralgia. Chronic pain syndromes, present for a mean duration of 4.9 years, occurred in 76 patients (48%) and included dysesthetic extremity pain (29%), back pain (14%), painful leg spasms (13%), and abdominal pain (2%). MS patients with pain were similar to the pain-free group in mean age of onset (34.0 versus 31.9 years), average duration of disease (13.3 versus 12.1 years), spinal cord involvement (97% for each group), and mean rating on Kurtzke Disability Status Scale (4.2 versus 3.5). They differed in sex ratio with a higher female-to-male ratio in the pain group (3:1 versus 1.4:1). Chronic pain is a common feature of well-established MS and is usually associated with a myelopathy. Therapy must be individualized for each specific pain syndrome.
We undertook a prospective study of 183 patients with monosymptomatic demyelination to determine the predictive value of the finding of cerebrospinal oligoclonal banding (OB) for the subsequent development of clinically definite multiple sclerosis. The results of this study indicate that patients with monosymptomatic demyelination who are OB positive are at significantly higher risk than those who are OB negative to develop clinically disseminated disease over the period of follow-up in this study. Positive OB is associated with a higher frequency of electrophysiological abnormalities than negative OB, suggesting that OB development correlates with the degree of biological dissemination. The observation that some patients develop OB during the course of the disease has practical implications for the follow-up of patients with unifocal disease and negative banding.
A 58-year-old woman had progressive visual failure in her left eye over a two-year period. Radiological investigation, including tomography and computerized tomographic (CT) scanning, did not result in a diagnosis. When no useful vision remained, surgical exploration disclosed an optic sheath meningioma. Complete recovery followed removal of the tumor.
Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans.
A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming. Here, we report DNA methylomics of archived Guthrie cards for the retrospective longitudinal analyses of in-utero-derived DNA methylation variation. We first validate two methodologies for generating comprehensive DNA methylomes from Guthrie cards. Then, using an integrated epigenomic/genomic analysis of Guthrie cards and follow-up samplings, we identify interindividual DNA methylation variation that is present both at birth and 3 yr later. These findings suggest that disease-relevant epigenetic variation could be detected at birth, i.e., before overt clinical disease. Guthrie card methylomics offers a potentially powerful and cost-effective strategy for studying the dynamics of interindividual epigenomic variation in a range of common human diseases.