Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder.

Ellis-van Creveld syndrome, an autosomal recessively inherited chondrodysplastic dwarfism, is frequent among Old Order Amish of Pennsylvania. Decades of longitudinal research on bipolar affective disorder (BPAD) revealed cosegregation of high numbers of EvC and Bipolar I (BPI) cases in several large Amish families descending from the same pioneer. Despite the high prevalence of both disorders in these families, no EvC individual has ever been reported with BPI. The proximity of the EVC gene to our previously reported chromosome 4p16 BPAD locus with protective alleles, coupled with detailed clinical observations that EvC and BPI do not occur in the same individuals, led us to hypothesize that the genetic defect causing EvC in the Amish confers protection from BPI. This hypothesis is supported by a significant negative association of these two disorders when contrasted with absence of disease (P=0.029, Fisher's exact test, two-sided, verified by permutation to estimate the null distribution of the test statistic). As homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. Understanding how disrupted Shh signaling protects against BPI could uncover variants in the Shh pathway that cause or increase risk for this and related mood disorders.

A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish.

The most characteristic features of bipolar affective disorder (manic-depressive illness) are episodes of mania (bipolar I, BPI) or hypomania (bipolar II, BPII) interspersed with periods of depression. Manic-depressive illness afflicts about one percent of the population, and if untreated, is associated with an approximately 20% risk of suicide. Twin, family and adoption studies provide compelling evidence for a partial genetic aetiology, but the mode(s) of inheritance has not been identified. Nonetheless, the majority of genetic linkage studies have assumed classical mendelian inheritance attributable to a single major gene. Although segregation analyses have yielded inconsistent results (with most studies rejecting a single locus inheritance model), the best single gene model is dominant inheritance if only BPI is considered. Reported linkages of bipolar affective disorder on chromosomes 11, 18, 21 and X have been difficult to substantiate, and additional studies are required for replication or exclusion of these regions. We now present the results of our genome-wide linkage analyses that provide evidence that regions on chromosomes 6, 13 and 15 harbour susceptibility loci for bipolar affective disorder, suggesting that bipolar affective disorder in the Old Order Amish is inherited as a complex trait.

Risks of affective illness among first-degree relatives of bipolar I old-order Amish probands.

Data from bipolar I old-order Amish families suggest that the morbid risk of illness is not significantly different in this population when compared with estimates of risk from previous studies. The age-corrected rates of bipolar I, bipolar II, and major depressive disorder among first-degree relatives are 8.7, 3.7, and 11.6, respectively. Risk of illness is not significantly different among male and female relatives and among relatives of male and female probands. Consistent with other reports, the rate of illness is higher among relatives of probands with early-onset disease. In contrast with previous reports, there does not appear to be a cohort effect in this population.

Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic "fingerprints".

Autoimmune thyroid disease is characterized by the tendency to cluster in families and by IgG class autoantibodies to antigens such as thyroid peroxidase (TPO). The epitopes recognized by polyclonal serum autoantibodies can be quantitatively fingerprinted using four recombinant human TPO autoantibodies (expressed as Fab) that define A and B domain epitopes in an immunodominant region. To determine whether these fingerprints are genetically transmitted, we analyzed fingerprints of 63 members of 7 multiplex Old Order Amish families and 17 individuals from 4 Hashimoto thyroiditis families. Inhibition of serum autoantibody binding to [125I]TPO by the recombinant Fab was used to assess recognition of the TPO immunodominant region (4 Fab combined) and recognition of domain A or B (individual Fab). Complex segregation analysis was performed using a unified model (POINTER). For the 4 Fab combined inhibition phenotype, the no transmission model was rejected (chi2(4) = 20.67; P < 0.0032), and the most parsimonious model includes a major gene effect. More importantly, evidence for genetic transmission was obtained for the phenotype defined by the ratio of inhibition by subdomain Fab B1:B2. Thus, for this ratio (reflecting recognition of the B domain), the no transmission model was rejected chi2(4) = 63.59; P < 0.000008). Moreover, the polygenic hypothesis could be rejected, but not the major locus hypothesis, suggesting that major genes might be involved in familial transmission of this trait. In conclusion, our findings suggest that autoantibody recognition of the TPO immunodominant region and the TPO B domain is genetically transmitted. These data may open the way to the identification by candidate analysis or positional cloning of at least one gene responsible for the development of Hashimoto's thyroiditis.

A linkage study of distal chromosome 5q and bipolar disorder.

There are well-established abnormalities of hypothalamic-pituitary-adrenal (HPA) axis and beta 2 adrenergic receptor function in affective disorders. The genes for the glucocorticoid receptor (GRL) and the beta 2 adrenergic receptor (ADRB2) have been cloned and mapped to distal chromosome 5q. In this study, we have examined polymorphisms of these two candidate genes and other nearby markers for linkage to bipolar disorder in Amish pedigree 110 and three large Icelandic pedigrees. These loci were tested for linkage in two-point and multipoint analyses using a model of autosomal dominant transmission with age-dependent reduced penetrance. Two-point analyses revealed a maximum LOD score of 1.14 at theta = 0.20 from GRL. Linkage could be excluded to ADRB2, as well as to three nearby anonymous markers, D5S207, D5S70, and D5S119. Analyses of another anonymous marker, D5S36, were inconclusive. Multipoint analyses excluded linkage to a 55 cM region including the interval between D5S207 and D5S36 and flanking regions, with the exception of a 7 cM interval between GRL and ADRB2. Despite the intriguing positive LOD score obtained with GRL, linkage to bipolar disorder could not be demonstrated in the region examined.

Amish Study, I: Affective disorders among the Amish, 1976-1980.

The authors review the goals, methods, sample, and selected epidemiologic findings from a collaborative study of affective disorders among the Amish. This culturally and genetically homogeneous population (N = 12,500) constitutes an excellent research setting for psychiatric epidemiologic and genetic study. Alcoholism, drug abuse, and sociopathy did not complicate the study because they are culturally prohibited. During 1976-1980, 112 active cases of mental illness were identified; 71% received diagnoses of major affective disorder. Equal numbers of men and women received diagnoses of unipolar illness, and slightly more men than women were diagnosed as having bipolar illness.

Amish Study, II: Consensus diagnoses and reliability results.

Reliability of diagnosis is central to genetic research on mental illness. In the Amish Study of affective disorders, consensus diagnoses were derived by a psychiatric board using the Research Diagnostic Criteria (RDC). To verify the reliability of diagnoses, the authors 1) studied how well board members followed RDC procedures, 2) compared diagnoses based on abstracted medical records with those based on full medical records, 3) compared diagnoses based on the two data sources--abstracted medical records and the Schedule for Affective Disorders and Schizophrenia-Lifetime Version--and 4) studied diagnostic stability to determine validity of diagnosis. The results of these substudies demonstrate a high concordance of diagnosis.

Amish Study, III: the impact of cultural factors on diagnosis of bipolar illness.

In the Amish Study of affective disorders, 79% of the 28 active bipolar I patients, diagnosed according to Research DIagnostic Criteria, previously had received hospital record diagnoses of schizophrenia. Both cultural and clinical factors hindered correct diagnosis, and cultural influences particularly complicated the interpretation of the manic symptoms of grandiosity and excessive involvement in activities. Other factors central to misdiagnosis were form of thought (flight of ideas), content of thought (grandiose and religious delusions), paranoid features, and the failure to recognize the presence of a manic syndrome.

Amish study, V: Lithium-sodium countertransport and catechol O-methyltransferase in pedigrees of bipolar probands.

The authors studied 87 individuals from four large Amish pedigrees to determine the relationship between susceptibility to affective disorders and variation in the measures of two biochemical variables, catechol O-methyltransferase (COMT) and lithium countertransport. Assays were done in duplicate and blind to diagnostic or pedigree status. Data were analyzed separately within families as well as by pooling ill and well subjects across pedigrees. Various statistical analyses yielded no significant differences in lithium measures or COMT activity levels between members diagnosed as having a form of affective disorder and the normal members.

Amish study, IV: Genetic linkage study of pedigrees of bipolar probands.

Genetic linkage studies were conducted on five Old Order Amish bipolar pedigrees in 1979 and 1982, with 94 members tested for color blindness and typed for 42 red blood cell and related markers in 17 antigen systems. Also, 59 individuals in two pedigrees were typed for HLA, Bf, and GLO. Linkage analyses assuming X-linkage and autosomal inheritance of bipolar illness were done with diagnostic schemes ranging from strict bipolar to milder forms of affective disorder. Linkage to affective disorders was not strongly supported for any marker locus. Close linkage to HLA was excluded, with weaker evidence against linkage to GLO.

A genetic linkage study of bipolar disorder and 13 markers on chromosome 11 including the D2 dopamine receptor.

Chromosome 11 is a region of great interest in the search for genes for bipolar disorder. Although an initial report of linkage to 11p15 was not replicated in numerous subsequent studies, the remainder of the chromosome contains a variety of interesting candidate genes and regions. These include the D2 dopamine receptor and the site of a chromosomal translocation that has been reported to be associated with bipolar disorder. As part of a systematic survey of the genome for markers linked to bipolar disorder, we have examined 13 markers on chromosome 11 in three large Icelandic families and Amish pedigree 110. No clear evidence of linkage was obtained. The highest lod score was found at D11S29 (lod = 1.63 at theta = 0.1), which is in the general region of the reported translocation breakpoints. However, this lod is not statistically significant, and its meaning is further mitigated by strongly negative lods in two nearby flanking markers. Linkage to the D2 dopamine receptor locus was strongly excluded (lod = -4.02 at theta = 0.0). In two-point analyses, linkage to bipolar disorder could be excluded to eight of the 13 markers. Multipoint analyses, similarly, failed to reveal any evidence of linkage.

Complex segregation analysis of antibodies to thyroid peroxidase in Old Order Amish families.

Autoimmune thyroid disease (AITD) may be characterized by the measurement in serum of antibodies to thyroid peroxidase. A population of Old Order Amish individuals and families was investigated to determine the prevalence of these antibodies and to examine hypotheses about the mode of transmission of thyroid antibodies. Complex segregation analyses were performed on 4 large multigenerational Old Order Amish families composed of 26 nuclear families containing 199 first degree relatives. Several alternative hypotheses of genetic transmission were examined. Hypotheses of no transmission, polygenic inheritance, single locus transmission, and mixed inheritance were compared. The analyses incorporated population prevalences obtained from a random sample of individuals. Results suggest that the pattern of transmission of thyroid antibodies in these families is consistent with a mixed model in which the major gene is transmitted in an autosomal dominant pattern. The mixed model postulates that there is a single gene of major effect as well as a polygenic component that can act separately and/or together to confer susceptibility for this phenotype. The parameter estimates for the major locus are: gene frequency (q), 0.16 +/- 0.01; maximum male penetrance, 0.35; and maximum female penetrance, 0.70. The heritability of the polygenic background is estimated at 0.41.

Complex segregation analyses of old order Amish families ascertained through bipolar I individuals.

Specific genetic hypotheses about the mode of transmission of bipolar affective disorders were examined by performing complex segregation analyses of Old Order Amish families. The analyses were performed on 1) the total set of 42 families including 689 relatives, 2) a subset of 19 families consisting of those kindreds sharing common ancestors within three generations that contained 333 relatives, and 3) a subset of 23 more distantly related families with 356 relatives. When all 42 families were included in the analyses, the specific mode of transmission that could be distinguished was dependent upon the diagnostic scheme used in the analysis. An autosomal dominant mode of inheritance could be rejected when relatives with bipolar I, atypical bipolar, major depressive disorder, and hypomania were included as affected. When analyses included only the subset of families more closely related, an autosomal dominant inheritance model was found to be consistent with transmission of BP I disorder. It was not possible to distinguish between other transmission models with broader diagnostic schemes in this subset of families. Finally, results of analyses on the subset of more distantly related families suggest that there is a significant proportion of Old Order Amish families in which the genetic factors contributing to the expression of bipolar illness are either polygenic or oligogenic.

Initial report of a genome search for the affective disorder predisposition gene in the old order Amish pedigrees: chromosomes 1 and 11.

Family data have suggested that some forms of major affective disorder are genetic. Certain of the Old Order Amish pedigrees have a familial form of the disease. In this report we present the results of genetic analyses under autosomal dominant mode of transmission with reduced penetrance and three different disease hierarchies. The pedigrees were genotyped with 28 markers from chromosome 1 and 23 markers from chromosomes 11. None of the markers result in a significantly positive lod score.

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.

Search for a gene that predisposes individuals to BPI disorder.

To determine the role of genetics in bipolar affective disorders it was necessary to have correct diagnoses and large homogenous population(s). To identify a marker linked to the disease two additional factors were important, a correct model for genetic transmission and highly polymorphic DNA markers. With the establishment of a linked marker the aim is to identify the susceptibility gene. Two approaches are the prediction of candidate genes and/or the determination of a physical map of the region.

Update on the search for DNA markers linked to manic-depressive illness in the Old Order Amish.

In this report we describe our efforts to identify a gene involved in bipolar illness using a large, multigenerational Old Order Amish pedigree with many affected individuals. The original collection of cell lines from Amish pedigree 110 has been extended to include 169 individuals. We have used over 250 markers spaced at approximately 20 centiMorgans that detect restriction length fragment polymorphisms, but no LOD scores greater than 3 have been obtained from pairwise linkage analyses. We are expanding our collection of cell lines from both normal and affected family members and updating our diagnostic data as we continue our systematic screening of the genome for a gene involved in bipolar illness.

Prodromal symptoms before onset of manic-depressive disorder suggested by first hospital admission histories.

OBJECTIVE: A priority for research on manic-depressive or bipolar I disorder (BPI) for children and adolescents has been to search for early predictors of the illness. METHOD: Medical record data were reviewed and systematically coded for a sample of 58 adult patients (32 males/26 females) with confirmed diagnoses of BPI to identify prodromal features and possible patterns of symptoms from the Amish Study. RESULTS: The most frequently reported symptoms included episodic changes in mood (depressed and irritable) and energy plus anger dyscontrol, with no significant gender differences. A progression of ages is seen for the most commonly reported symptoms prior to age 16. The time interval was 9 to 12 years between appearance of the first symptoms and onset of a documented BPI syndrome. CONCLUSIONS: The data suggest testable hypotheses about specific symptoms and behaviors that may be useful for the early detection of children at highest risk for developing manic-depressive disorder.

Reliability and relationship of various ages of onset criteria for major affective disorder.

This paper presents data on six different clinical definitions (indices) of age of onset for major affective disorders. The inter-rater reliability for each index and the relationships among these indices are discussed. Age of onset for impairment with affective symptoms was found to be a reliable and useful index of early onset. It discriminated between unipolar depressed subjects and both bipolar I and bipolar II subjects.