Biomedical subjects

A D Sadovnick

Publications and source records attributed to A D Sadovnick.

At least 55 records · Page 3Linked to original sources

PubMed1998

Ethical guidelines of the Alzheimer Society of Canada.

Alzheimer's disease raises numerous ethical issues which vary and evolve over the course of the illness. In recognition of the need for ongoing discussion of these issues, the Alzheimer Society of Canada established a Task Force on Ethics in 1995. Through a process of "discourse ethics" and consultation on a national scale, the Task Force produced a series of guidelines dealing with the issues of: communicating the diagnosis, driving, respecting individual choice, quality of life, participation in research, genetic testing, the use of restraints, and end-of-life care. This manuscript presents a summary of these guidelines as well as a summary of the ideas on which they were based. It was the hope of the Society that the publication of these guidelines will serve to facilitate discussion of the ethics of care of those with Alzheimer's disease.

Alzheimer Disease↗

PubMed1998

Effect of age at onset and parental disease status on sibling risks for MS.

MS is believed to be a complex trait determined by genetic and nongenetic factors. Data suggest that MS susceptibility and age at onset are each, at least to some extent, under genetic control. The present study carefully examined five covariates (sex of the index case, sex of the sibling, birth cohort of the sibling [< or = 1919, 1920 to 1939, > or = 1940], age of MS onset in the index patient (< or = 20 years, 21 to 30 years, 31 to 40 years, > 40 years), and MS disease status of the parents [i.e., MS present in one parent or no parent with MS]) that may influence the familial risk of MS in a large cohort of 1,896 MS patients and 8,878 of their first-degree relatives. Of these, sex of the sibling, parental MS status, and index patient onset age were the important factors influencing MS risks to siblings. The results of this study are (1) the index-patient-onset-age effect suggests that individuals with a greater genetic loading (i.e., a greater contribution of susceptibility alleles) have an earlier age at onset and (2) genetic loading is substantially increased in individuals with an affected parent. These data are important both for genetic counseling and gene identification studies.

Adult↗

PubMed1997

Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22.

Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. Four additional markers were subsequently typed in selected positive families, and yielded positive lods at 6 of 7 markers spanning 18 cM in this region. Nonparametric, multipoint analyses using the affected pedigree member (APM) method also yielded suggestive evidence for linkage in both the UCSD/UBC family set (P = 0.0024) and in the combined families (P = 0.017). Affected sibpair analyses were similarly positive in the UCSD/UBC families (P = 0.017), and in the combined families (P = 0.004). These results are suggestive of a possible locus for bipolar disorder near the VCFS region on chromosome 22.

Abnormalities, Multiple↗

PubMed1997

Update on management and genetics of multiple sclerosis.

Although the exact etiology of multiple sclerosis (MS) remains uncertain, there is an increasing body of evidence to support the role of genetic factors in MS susceptibility in general and the familial aggregation of MS in particular. MS.management continues to be largely symptom-specific. MS relapses are now frequently treated with IV-methylprednisone. In recent years, MS treatment trials are being conducted throughout the world. Interferon beta-1b has been approved as the first ongoing therapy for relapsing/remitting MS, although some issues/concerns remain to be addressed. In summary, while much research is still needed, important progress is being made in unravelling the etiology of MS and in developing management protocols which are not symptom- or relapse-specific.

Activities of Daily Living↗

PubMed1997

Genetics of multiple sclerosis.

Multiple Sclerosis (MS) is a common chronic central nervous system disease in young adults. Relative familial risk appears to be determined largely by genes while population risk is strongly influenced by environmental factors. This is supported by genetic epidemiological studies which also suggest an oligogenic inheritance of susceptibility. The HLA DRB1*1501, DQA1*0102, DQB1 0602 haplotype is associated with the disease but HLA contributes only modestly to overall susceptibility. The results of three genomic searches are concordant with the genetic epidemiology and imply a number of genes with interacting effects will be found. Importantly, no single region has been identified with a major influence on familial risk.

Adult↗

PubMed1997

Genetic epidemiology of multiple sclerosis.

The continuing search for genetic loci which may influence multiple sclerosis susceptibility has probably been more complex and exciting than Spielman and Nathanson (4) could have imagined in 1982. Restriction fragment length polymorphisms no longer represent the "cutting edge" of technology. This entire area of research has gained incredible impetus with advances in molecular genetics and the advent of the "Human Genome Project." Readers must be cautioned that identification of a gene does not equate with a cure. Nevertheless, we are entering into a very exciting era with respect to the genetics and treatment of common complex disorders such as breast cancer, Alzheimer disease, and multiple sclerosis. Given the increasing awareness of the public about the role of genetics in the etiology of such disorders, a better understanding is needed of the legal, social, ethical, and psychologic implications of genetic research in multiple sclerosis.

Epidemiologic Studies↗

PubMed1997

Risks of multiple sclerosis in relatives of patients in Flanders, Belgium.

OBJECTIVES: To calculate age adjusted risks for multiple sclerosis in relatives of Flemish patients with multiple sclerosis. METHODS: Lifetime risks were calculated using the maximum likelihood approach. RESULTS: Vital information was obtained on 674 probands with multiple sclerosis in Flanders and a total of their 26225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21351 (81.4%) relatives. The age adjusted risk for parents was 1.61 (SEM 0.35)%, for siblings 2.10 (SE 0.36)%, and for children 1.71 (SEM 0.70)%. For aunts and uncles, the risk was 0.66 (SEM 0.13)%. CONCLUSIONS: The risk for first degree relatives of patients with multiple sclerosis in Flanders is increased 10-fold to 12-fold; for second degree relatives, it is increased threefold. This information can be used for risk counselling in families and provides additional support for the role of more than one locus contributing to the susceptibility of multiple sclerosis.

Adult↗

PubMed1996

Possible locus for bipolar disorder near the dopamine transporter on chromosome 5.

The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission by mediating the active reuptake of synaptic dopamine. It is an important candidate gene for bipolar disorder because of data implicating dopamine abnormalities in mania, and because it is the site of action of amphetamine, which has activating and psychotogenic properties. DAT has recently been cloned by its homology to a family of transporters, and mapped to chromosome 5p15.3. We tested DAT for linkage to bipolar disorder in a collection of 21 families from the general North American population (University of California, San Diego/University of British Columbia [UCSD/UBC] families), three Icelandic pedigrees, and Old Order Amish pedigree 110. We examined three markers at DAT, including a 5' TaqI RFLP (HDAT-TaqI), a highly polymorphic variable number of tandem repeats marker (VNTR) (HDAT-VNTR1), and a 3' 40-bp repeat marker (HDAT-PCR1), as well as two nearby microsatellite markers, D5S392 and D5S406. A maximum lod score of 2.38 was obtained at D5S392 in one of the UCSD/UBC families under an autosomal-dominant model. A lod score of 1.09 was also obtained under the same dominant model in the Amish at HDAT-PCR1. In the combined set of families, a maximum lod score of 1.76 was obtained under an autosomal-recessive model at HDAT-TaqI. Positive results were also obtained at several markers, using three nonparametric methods in the UCSD/UBC family set: the affected pedigree member method (P = 0.001), an affected sib pair method (ESPA, P = 0.0008), and the transmission disequilibrium test (P = 0.024). These results suggest the presence of a susceptibility locus for bipolar disorder near the DAT locus on chromosome 5.

Bipolar Disorder↗

PubMed1996

Major depression, minor depression, and double depression: are they distinct clinical entities?

The clinical concept of "double depression," i.e., the superimposition of a major depressive disorder in a patient with dysthymic disorder, implies that there are at least some differences between dysthymia, major depression, and double depression. However, the relationship between these two syndromes remains unclear. The present study uses genetic methodology to explore any possible relationship between minor depression, double depression, and major depression. From 1988-1990, all consecutive unrelated inpatients and outpatients (index cases) presenting to a university-based mood disorders service had detailed family histories taken, using modification of the "family history method." Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria. For all index cases with a diagnosis of minor or intermittent depression, and minor/intermittent depression plus either single or recurrent depression ("double depression"), morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, and children) using the maximum likelihood approach. Results showed no significant differences in morbidity risk calculations to first-degree relatives of index cases with minor/intermittent depression, major depression, or double depression. The data from this genetic perspective suggest that single depression, recurrent depression, minor depression, and double depression are indistinguishable.

Depression↗

PubMed1996

Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.

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<0.001; likelihood ratio test). There were no significant differences in risk for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for those raised together versus those raised apart from the index case (1.17 percent vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the feasibility of using half-sib studies to throw light on the aetiology of complex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as intrauterine and perinatal factors, breastfeeding, and genomic imprinting) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an observation consistent with a polygenic hypothesis.

Canada↗

PubMed1996

Genetic linkage study of bipolar disorder and the serotonin transporter.

The serotonin transporter (HTT) is an important candidate gene for the genetic transmission of bipolar disorder. It is the site of action of many antidepressants, and plays a key role in the regulation of serotonin neurotransmission. Many studies of affectively ill patients have found abnormalities in serotonin metabolism, and dysregulation of the transporter itself. The human serotonin transporter has been recently cloned and mapped to chromosome 17. We have identified a PstI RFLP at the HTT locus, and here report our examination of this polymorphism for possible linkage to bipolar disorder. Eighteen families were examined from three populations: the Old Order Amish, Iceland, and the general North American population. In addition to HTT, three other microsatellite markers were examined, which span an interval known to contain HTT. Linkage analyses were conducted under both dominant and recessive models, as well as both narrow (bipolar only) and broad (bipolar + recurrent unipolar) diagnostic models. Linkage could be excluded to HTT under all models examined. Linkage to the interval spanned by the microsatellites was similarly excluded under the dominant models. In two individual families, maximum lod scores of 1.02 and 0.84 were obtained at D17S798 and HTT, respectively. However, these data overall do not support the presence of a susceptibility locus for bipolar disorder near the serotonin transporter.

Bipolar Disorder↗

PubMed1996

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Chromosome Mapping↗

PubMed1996

Depression and multiple sclerosis.

The objective of the present study were (1) to ascertain the lifetime risk of a depression in a representative group of multiple sclerosis (MS) patients, (2) to assess the morbidity risks for depression among first-degree relatives of these MS patients, and (3) to compare these familial risks for first-degree relatives of MS patients with those for first-degree relatives of a primary depression population, i.e., depression but no MS. We psychiatrically evaluated 221 MS patients (index cases) using a structured clinical interview for the DSM-III-R and calculated the rate and lifetime risk of depression for these index cases using the product limit estimate of survival function. We obtained psychiatric histories for all first-degree relatives of index cases, and we calculated morbidity risks for depression for these relatives using the maximum likelihood approach and compared the risks using the likelihood ratio tests. Index cases had a 50.3% lifetime risk of depression. Morbidity risks for depression among first-degree relatives of index cases were decidedly lower when compared with morbidity risks among first-degree relatives of the reference population. Although there appears to be a very high rate of depression among MS patients, the data for their first-degree relatives do not support a clear genetic basis for this depression, or at least the same genetic basis that probably operates within families when depression occurs in the absence of MS.

Adolescent↗

PubMed1996

Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old?

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

Age Factors↗

PubMed1995

Bipolar disorder: evidence for a major locus.

Complex segregation analyses were conducted on families of bipolar I and bipolar II probands to delineate the mode of inheritance. The probands were ascertained from consecutive referrals to the Mood Disorder Service, University Hospital, University of British Columbia and diagnosed by DSM-III-R and Research Diagnostic Criteria. Data were available on over 1,500 first-degree relatives of the 186 Caucasian probands. The purpose of the analyses was to determine if, after correcting for age and birth cohort, there was evidence for a single major locus. Five models were fit to the data using the statistical package SAGE: i) dominant, ii) recessive, iii) arbitrary mendelian inheritance, iv) environmental, and v) no major effects. A single dominant, mendelian major locus was the best fitting of these models for the sample of bipolar I and II probands when only bipolar relatives were defined as affected (polygenic inheritance could not be tested). Adding recurrent major depression to the diagnosis "affected" for relatives reduced the evidence for a major locus effect. Our findings support the undertaking of linkage studies and are consistent with the analyses of the National Institutes of Mental Health (NIMH) Collaborative Study data by Rice et al. (Arch Gen Psychiatry 44: 441-447, 1987) and Blangero and Elston (Genet Epidemiol 6:221-227, 1989).

Bipolar Disorder↗

PubMed1995

A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group.

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.

Adoption↗

PubMed1995

Sibling risks of abdominal aortic aneurysm.

There is evidence that the risk of abdominal aortic aneurysm (AAA) is greater in first-degree relatives of patients with the disorder than in the same age group of the general population. We conducted a 3-year study of siblings of AAA probands and siblings of a control group (cataract surgery patients) of the same age. Genetic information was obtained by interview from 126 probands and 100 controls; another family member was present at the interview. Medical records were obtained and further information verified before a sibling (over age 50) was assigned affected status. Of 427 siblings of probands, 19 (4.4%) had probable or definite AAA, compared with five (1.1%) of 451 siblings of controls. The lifetime cumulative risks of AAA at age 83 were 11.7% (SD 3.1) and 7.5% (4.1), respectively. The risk of AAA began at an earlier age and increased more rapidly for probands' siblings than for controls' siblings (p < 0.01, log-rank test). A risk comparison, based on the results of ultrasound screening of 54 geographically accessible siblings of probands and the 100 controls showed a similar pattern. Ten (19%) siblings of probands and eight (8%) controls had AAA on ultrasound (lifetime cumulative risk 60.8% [18.9] vs 14.9% [5.1], p = 0.01). These results show that familial factors influence the age of onset of AAA. We recommend routine ultrasound examination of siblings of patients with AAA.

Age Factors↗

PubMed1995

Is sporadic MS caused by an infection of adolescence and early adulthood? A case-control study of birth order position.

Birth order position was examined in 164 cases with sporadic multiple sclerosis (MS), i.e. no other family members with MS, and spousal controls, matched for sibship size, socioeconomic status and opposite sex. The results did not find an association between birth order position and the subsequent development of MS and thus do not support the concept of an infectious cause for MS where "early exposure" is protective and exposure to the infection is a single event of short duration.

Adolescent↗