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Several groups have reported evidence suggesting linkage of bipolar affective disorder (BPAD) to chromosome 18. We have reported data from 28 pedigrees that showed linkage to marker loci on 18p and to loci 40 cM distant on 18q. Most of the linkage evidence derived from families with affected phenotypes in only the paternal lineage and from marker alleles transmitted on the paternal chromosome. We now report results from a series of 30 new pedigrees (259 individuals) genotyped for 13 polymorphic markers spanning chromosome 18. Subjects were interviewed by a psychiatrist and were diagnosed by highly reliable methods. Genotypes were generated with automated technology and were scored blind to phenotype. Affected sib pairs showed excess allele sharing at the 18q markers D18S541 and D18S38. A parent-of-origin effect was observed, but it was not consistently paternal. No robust evidence of linkage was detected for markers elsewhere on chromosome 18. Multipoint nonparametric linkage analysis in the new sample combined with the original sample of families supports linkage on chromosome 18q, but the susceptibility gene is not well localized.

Mutations in mitochondrial DNA (mtDNA) are implicated in the pathophysiology of affective disorders. To determine whether the 4977-base-pair deletion in mtDNA is more frequent in affective disorders, we quantitated the concentration of this deletion in leukocyte mtDNA in 34 probands with affective disorders (20 bipolar and 14 unipolar) and 20 controls. We found no significant difference in the quantitative ratio of deletion to wild-type mtDNA between patients and controls. One patient with unipolar depression and 1 of 2 patients previously reported as having a large quantity of the deleted mtDNA did have a markedly high ratio; however, the deletion did not segregate with the disease in these two families. These results do not support a hypothesis that the 4977-base-pair deletion plays an important role in the pathophysiology of affective disorders.

A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.

We report on an initial genome screen of 540 individuals from 97 families collected as part of the NIMH Genetics Initiative Bipolar Group. Among the individuals studied, 232 were diagnosed with bipolar (BP) I, 72 with BPII, 88 with major depressive disorder-recurrent type (UPR), and 32 with schizoaffective disorder, bipolar type (SA/BP). A total of 53 markers on chromosomes 2, 11, 13, 14, and X (average spacing: 11.5 cM) were studied at Johns Hopkins University. Tests for linkage were performed using nonparametric affected sib-pair and whole pedigree methods with three definitions of affected status. Three regions of interest were identified (13q14-32, Xp22, and Xq26-28). On chromosomes 2, 11, and 14, a disease locus with relative risk lambda(i) = 1.5 could be excluded in <10% of the genetic distance studied, while a locus conferring lambda(i) = 3 or greater could be excluded across at least 96%. The autosomal region that could not be excluded even with lambda(i) = 5 was near 13q14-32. In this region, two-point affected sib-pair analyses revealed a pair of consecutive loci with excess sharing (P < 0.05) and a multipoint affected sib-pair LOD score of 1.12. On the X chromosome, nonparametric multipoint affected sib-pair analyses revealed peak total LOD scores of 0.94 on Xp22 and 1.34 on Xq26-28. A locus linked to the markers in Xp22 would have lambda(i) = 3.6 in affected brother-brother pairs, while a locus linked to the markers in Xq26-28 would have lambda(i) > 1.9 in affected sister-sister pairs. The results on 13q14-32, Xp22, and Xq26-28 suggest areas of interest for further studies.

This study examines G-olf alpha as a possible candidate gene for susceptibility to bipolar affective disorder (BPAD) using the Transmission Disequilibrium Test (TDT). G-olf alpha, which encodes a subunit of a G-protein involved in intracellular signaling, maps within a region of chromosome 18 that has been implicated by two different linkage studies as a potential site of BPAD susceptibility loci. The expression pattern of G-olf alpha in the brain, its coupling to dopamine receptors, and the effects of lithium salts on G-proteins all support G-olf alpha as a candidate gene for BPAD. Our study population consisted of 106 probands and sibs with bipolar I disorder, with a median age-at-onset of 21.5 years ascertained from the United States. There was no evidence of linkage disequilibrium between BPAD and any of the observed G-olf alpha alleles in our sample. Division of families based on sex of the transmitting parent did not significantly change the results. This sample had good power (78%) to detect linkage disequilibrium with alleles conferring a relative risk equal to that estimated for the putative 18p locus (2.58). Our results do not support a major role for G-olf alpha as a susceptibility locus for BPAD in a substantial portion of our sample. Other genes lying near G-olf alpha within the linked region on chromosome 18 cannot be excluded by our data. This study illustrates the use of the TDT in evaluating candidate genes within linked chromosome regions.

The two most consistent features of the diseases caused by trinucleotide repeat expansion-neuropsychiatric symptoms and the phenomenon of genetic anticipation-may be present in forms of dementia, hereditary ataxia, Parkinsonism, bipolar affective disorder, schizophrenia and autism. To identify candidate genes for these disorders, we have screened human brain cDNA libraries for the presence of gene fragments containing polymorphic trinucleotide repeats. Here we report the cDNA cloning of CAGR1, originally detected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bp open reading frame encoding 359 amino acids. This amino acid sequence is homologous (56% amino acid identify and 81% amino acid conservation) to the Caenorhabditis elegans cell fate-determining protein mab-21. CAGR1 is expressed in several human tissues, most prominently in the cerebellum, as a message of approximately 3.0 kb. The gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are available to link the long repeat to this clinical phenotype, an expansion mutation of the CAGR1 repeat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.

A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q: at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = 0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; phi = 0.0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study..

The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017). In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.

Erythropoietin (EPO) is the primary hormone responsible for the growth and maturation of red blood cells in mammals. In contrast to many other growth factors, the specificity of EPO for mature erythroid cells has lead to its development as a safe and efficacious therapeutic, EPREX. The medical benefits of EPREX have been well established in the treatment of anaemic chronic renal failure patients, anaemic HIV patients treated with AZT, cancer chemotherapy patients, and patients wishing to donate their own blood prior to elective surgery (autologous predonation). Due to the chronic nature of EPO therapy, it would be desirable to have an orally administered 'second generation' molecule. An understanding of the structural basis of the interaction of EPO with its receptor will aid in the design of an oral anaemia drug. In this study, a series of mutations have been generated in a truncated form of the receptor comprising the extracellular region, termed EPO binding protein (EBP). One mutant, in which alanine replaces phenylalanine at position 93 (F93A) has a 500-fold reduction in binding compared to wild-type EBP. A neutralizing anti-EBP antibody binds poorly to the F93A mutant, while a non-neutralizing anti-EBP antibody binds wild-type and F93A equally well. Information from this mutational analysis can be applied to a receptor 3-D model and ultimately used in drug development.

Objective: The authors analyzed data from a family sample ascertained for a genetic linkage study of bipolar disorder to address the following questions: Do the major clinical subtypes of familial affective disorder have distinct distributions of age at onset? What factors other than clinical subtype affect these distributions? After controlling for these factors, do the differences in age at onset persist among the subtypes?, Methods: Eighty-two families were ascertained through a treated proband with bipolar disorder who had a family history of two or more affected siblings or one affected sibling and one affected parent. After participating in an interview conducted by a psychiatrist using the Schedule for Affective Disorders and Schizophrenia--Lifetime Version, 274 probands and their first-degree relatives were diagnosed as having bipolar I, bipolar II, or recurrent unipolar disorder according to Research Diagnostic Criteria. Age at first major affective episode and other clinical data were collected., Results: Onset age distributions were similar for bipolar I and bipolar II disorder but significantly different for recurrent unipolar disorder. This finding persisted after adjustment for a significantly earlier onset among females. Subjects with affective disorder in both parental lines (bilineal) also experienced a significantly earlier onset. Substance abuse, physical illness, and sex of the affected parent had no significant impact on onset age., Conclusions: Although differences in age at onset may reflect several factors, these results provide indirect support for the view that bipolar I and bipolar II disorders are genetically related phenotypes and suggest that bilineal families may be more complex than previously assumed.

Anticipation refers to the increase in disease severity or decrease in age at onset in succeeding generations. This phenomenon, formerly ascribed to observation biases, correlates with the expansion of trinucleotide repeat sequences (TNRs) in some disorders. If present in bipolar affective disorder (BPAD), anticipation could provide clues to its genetic etiology. We compared age at onset and disease severity between two generations of 34 unilineal families ascertained for a genetic linkage study of BPAD. Life-table analyses showed a significant decrease in survival to first mania or depression from the first to the second generation (P < .001). Intergenerational pairwise comparisons showed both a significantly earlier age at onset (P < .001) and a significantly increased disease severity (P < .001) in the second generation. This difference was significant under each of four data-sampling schemes which excluded probands in the second generation. The second generation experienced onset 8.9-13.5 years earlier and illness 1.8-3.4 times more severe than did the first generation. In additional analyses, drug abuse, deaths of affected individuals prior to interview, decreased fertility, censoring of age at onset, and the cohort effect did not affect our results. We conclude that genetic anticipation occurs in this sample of unilineal BPAD families. These findings may implicate genes with expanding TNRs in the genetic etiology of BPAD.

Objective: The purpose of this study was to compare the pattern of affective psychopathology in families ascertained for genetic linkage studies through bipolar I probands to that in families ascertained through bipolar II probands., Method: All available first-degree relatives (N = 266) of 48 bipolar I and eight bipolar II probands were interviewed with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version by one of two psychiatrists who had attained high interrater reliability for bipolar II disorder and other diagnoses., Results: Bipolar II disorder was the most common affective disorder in both family sets. Forty percent of the 47 first-degree relatives of the bipolar II probands and 22% of the 219 first-degree relatives of the bipolar I probands were diagnosed with bipolar II disorder. On the other hand, only one bipolar I relative was found in the bipolar II families., Conclusions: Bipolar II disorder was the most prevalent affected phenotype in both bipolar I and bipolar II families and was the only expressed phenotype in half of the bipolar II families. This suggests that bipolar II disorder is genetically related to but less complex than bipolar I disorder. Accurate diagnosis of bipolar II disorder may be crucial in finding the genetic loci underlying bipolar disorders generally.

In a previous study, we reported that a specific size cortical suction lesion of the right posterior cortex in rats produced hyperactivity and increased concentrations of dopamine in the nigrostriatal pathway. The present study extended those findings by addressing whether this phenomenon is lateralized to the right posterior cortex and whether the increases in nigrostriatal dopamine are necessary for the behavioral changes produced by the lesion. Right posterior cortical lesions of 1.8 mm diameter produced spontaneous hyperactivity over a 30-day postoperative period while identically placed 1.3 mm or 2.4 mm diameter lesions did not. Left hemisphere lesions of 1.3 mm, 1.8 mm or 2.4 mm diameter also failed to produce hyperactivity. The hyperactivity response to 1.8 mm diameter lesions of the right posterior cortex was not blocked by 70% depletions in nigrostriatal dopamine produced by bilateral nigral injections of 6-hydroxydopamine two weeks prior to cortical lesions. These findings suggest that hyperactivity following right posterior cortical lesions is lateralized and is not dependent upon changes in the nigrostriatal dopaminergic pathway.