We have evaluated genetic and environmental influences in multiple sclerosis (MS) by comparing age of onset in 99 sibling pairs concordant for the disease. We used three methods of analysis: (1) comparison of mean differences in age of onset and year of onset, (2) linear regression of differences in age or year of onset vs difference in ages, and (3) intraclass correlation of age of onset which is also used for monozygotic twins concordant for MS. Comparison of the mean differences in age of onset or year of onset is found to be inappropriate and potentially misleading. No significant results were found in linear regression of the age of onset or year of onset vs differences in ages, although a trend towards onset at the same age is present. However, nontwin siblings show a significant intraclass correlation for age of onset (P less than 0.01) as is seen in genetic disorders. A stronger intraclass correlation in age of onset in concordant monozygotic twins vs concordant sibling pairs further suggests that age of onset is partly under genetic control, assuming common exposure to an environmental agent. The results give little support for common exposure to an environmental trigger in concordant MS sibling pairs. They are consistent with a mixture of random independent exposures and common exposures leading to the development of the disease, with the former predominating.
Microchimerism, the persistence of foreign cells thought to derive from previous pregnancies, has been associated with autoimmune diseases. A maternal parent-of-origin effect in MS remains unexplained. We tested for microchimerism in monozygotic and dizygotic twin-pairs with MS. Microchimerism was associated with MS in affected females from monozygotic concordant pairs when compared to both affected (p=0.020) and unaffected (p=0.025) females in monozygotic discordant pairs. Microchimerism was increased in affected females of dizygotic discordant pairs (p=0.059). The rate of microchimerism was significantly higher in affected twins than in unaffected co-twins (p=0.0059). These observations show an association in twins between the presence of microchimerism and having MS.
To characterize the neuropsychiatric symptoms (NPS) of subjects classified as not cognitively impaired (NCI), cognitively impaired-not demented (CIND), and dementia.
A Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD) is a longitudinal investigation of individuals referred to eight Canadian dementia centers for evaluation of cognitive impairment and neurobehavioral symptoms. Of the inception cohort of 804 subjects for whom the informant-based Neuropsychiatric Inventory (NPI) was completed at study entry, 35 were classified as NCI, 193 as CIND, and 576 as dementia. The three diagnostic groups were compared on each of the 12 NPI items. Within each diagnostic group, comparisons were also made between symptomatic (NPS+; total score > 1) and asymptomatic (NPS-; total score = 0) subjects on measures of general cognitive status and functional disability. A subset of the NCI and CIND individuals were also compared on a comprehensive neuropsychological test battery.
There was at least one NPI item reported in 60% of subjects with NCI, 74% with CIND, and 89% with dementia. The item scores for delusions, hallucinations, agitation, apathy, disinhibition, aberrant motor behavior, and problems with appetite were greater in dementia subjects than in NCI or CIND. There were no significant differences between subjects with NCI and CIND on any NPI item. For each diagnostic group, NPS+ subjects were more impaired on functional but not neuropsychological measures.
Across all levels of cognition, neuropsychiatric symptoms (NPS) are an important feature in individuals referred to dementia clinics. The current data suggest that NPS may precede cognitive deficits in individuals classified as not cognitively impaired and cognitively impaired-not demented.
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.
Comment In: Ann Neurol. 2001 Oct;50(4):552-311601510
BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the contributions of genes and environment is to study half-sibs. METHODS In a Canadian population-based sample of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was reported by 939 index cases. By interview we elicited information on family structure and an illness in half-sibs and any full brothers or sisters. FINDINGS The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32 percent compared with 3.46 percent for the 1395 full sibs of the same cases (p
Kaplan-Meier risks estimates are calculated and compared for two consecutive series (N1 = 840, N2 = 819) of first-degree relatives of Alzheimer disease (AD) patients diagnosed as either "probable" or "autopsy-confirmed" AD. The consistency of results increases confidence in estimates and suggests consistent case ascertainment over 8 years. Lifetime risk estimates to age 88 for the combined sample (23.4% +/- 3.0%) do not approach the 50% risk compatible with an autosomal dominant model of transmission. These results support our previous finding and suggest that an autosomal dominant gene(s) is not responsible for all cases of AD.
Genetic-environmental interactions probably underlie spontaneous human autoimmune disorders, a category of complex traits thought to include multiple sclerosis (MS). The geographical distribution and familial aggregation of this disease have often been ascribed to the role of infectious agents, but there is no consensus. Increased family risks range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives over the general population prevalence of 0.1% (ref. 6). We screened a population-based sample of 15,000 individuals with MS by using standardized, personally administered questionnaires to identify adopted index cases and/or those who had adopted relatives. The frequency of MS among first-degree non-biological relatives living with the index case was no greater than expected from Canadian population prevalence data and significantly less than for biological relatives. These findings indicate that familial aggregation of MS is genetically determined: no effect of shared environment was detectable.
Since the inception of the MS Clinic, Vancouver Hospital and Health Sciences Centre, all consecutive, unrelated patients with multiple sclerosis (MS) have had their family histories documented by the Clinic's geneticist as part of the overall assessment. The family histories are updated annually. These data, along with the longitudinal clinical information on each patient, have resulted in a unique resource for clinical genetic/genetic epidemiological/molecular genetic research on MS. Analyses of these data have included the calculation of age-adjusted familial risks for MS; genetic modeling, necessary for molecular genetic research; and family studies involving affected relative pairs, studies of the nontransmitted parental haplotypes, and multiplex families. The results of the work to date are discussed. In addition, the impact of these data on the development of the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis is reviewed. This project involves all 14 MS "sites" across Canada, and the study's overall objective is to elucidate the roles of genetic and environmental factors in the causation of MS.
Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P
Bipolar disorder or manic depressive illness is a major psychiatric disorder that is characterized by fluctuation between two abnormal mood states. Mania is accompanied by symptoms of euphoria, irritability, or excitation, whereas depression is associated with low mood and decreased motivation and energy. The etiology is currently unknown; however, numerous family, twin, and adoption studies have argued for a substantial genetic contribution. We have conducted a genome survey of bipolar disorder using 443 microsatellite markers in a set of 20 families from the general North American population to identify possible susceptibility loci. A maximum logarithm of odds score of 3.8 was obtained at D22S278 on 22q. Positive scores were found spanning a region of nearly 32 centimorgans (cM) on 22q, with a possible secondary peak at D22S419. Six other chromosomal regions yielded suggestive evidence for linkage: 3p21, 3q27, 5p15, 10q, 13q31-q34, and 21q22. The regions on 22q, 13q, and 10q have been implicated in studies of schizophrenia, suggesting the possible presence of susceptibility genes common to both disorders.
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