A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on approximately 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0. 000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2. 67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0. 00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees.

We have investigated whether there is a locus on chromosome 6 that confers an increased susceptibility to schizophrenia using a two-stage approach and nonparametric linkage analysis. Allele sharing identical by descent (IBD) and multipoint maximum likelihood score (MLS) statistics were employed. Results from two tested data sets, a first data set, or genome scanning data set, and a second replication data set, show excess allele sharing for multiple markers in 6q, a chromosomal region not previously reported as linked to schizophrenia. In our genome scanning data set, excess allele sharing was found for markers on 6q13-q26. The greatest allele sharing was at interval 6q21-q22.3 at marker D6S416 (IBD percentage 69; P = 0.00024). The multipoint MLS values were greater than 2.4 in the 11.4-cM interval delimited by D6S301 and D6S303, with a maximum value of 3.06 close to D6S278 and of 3.05 at D6S454/D6S423. We did not confirm, however, the previously described linkage in 6p, when tested in the systematic genome scanning data set. The replication data set also showed excess allele sharing in chromosomal area 6q13-q26, which overlapped with the aforementioned positive linkage area of the genome scanning data set. The highest sharing of the second data set was at D6S424 (IBD percentage 64; P = 0.0004), D6S283 (IBD percentage 62; P = 0.0009), and D6S423 (IBD percentage 63; P = 0.0009). Multipoint MLS analysis yielded MLS values greater than 1 in an area of about 35 cM, which overlaps with the MLS multipoint area of linkage from the genome scanning data set. The multipoint MLS at the D6S454/D6S423 locus was 2.05. In the second data set, the maximum multipoint MLS was located about 10 cM centromeric from the maximum of the genome scanning data set, at the interval D6S424-D6S275 (2.35). Our results provide very suggestive evidence for a susceptibility locus for schizophrenia in chromosome 6q from two independent data sets.

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q.

An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (approximately 68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 (P < 0.05) on 4p, D4S1647 (P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 (P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q (P < 0.05). In addition, five markers on 7q displayed increased IBD sharing (P = 0.046-0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing (P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an approximately 9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing (P = 0.041-0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing (P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q.

A linkage study of bipolar illness.

BACKGROUND: Although genetic epidemiological studies of bipolar (BP) illness are consistent with a heritable component, inherited risk factors remain unknown. The goal of the present study is to describe the localization of BP susceptibility loci through linkage strategies, including a genome-wide search. METHODS: A linkage study of 22 BP families has been performed. These BP families include almost 400 persons, 173 of whom have been diagnosed as having BP I, schizoaffective, BP II with major depression, or recurrent unipolar illness. Using an autosomal dominant disease model with 85% or 50% age-dependent penetrance, and a recessive model with 85% penetrance, linkage analyses were performed assuming a narrow (BP and schizoaffective) or a broad (BP, schizoaffective, or unipolar) definition of the BP spectrum. Affected sibling pairs and affected pedigree member analyses were performed when positive lod scores were observed in multiple pedigrees. The present article describes linkage analysis of 310 DNA markers on chromosomes 1, 5p, 6, 8, 10q, 11q, and 12 to 18. RESULTS: None of the loci examined disclosed compelling evidence for linkage using lod score analyses. Model-independent analysis by multilocus affected pedigree member method in the pericentromeric chromosome 18 region disclosed statistically significant evidence (P < .0001) for a BP susceptibility gene in this region. Multilocus analysis by affected sibling pair method also disclosed evidence for linkage (P < .00008). CONCLUSIONS: Our results imply that a BP susceptibility gene exists near the centromere of chromosome 18. Confirmation of this finding (by independent investigators studying different pedigrees) has been published, suggesting that a valid BP disease linkage may have been discovered.

Psychiatric disorders in the first-degree relatives of probands with bulimia nervosa.

Data from a family study of psychiatric disorders showed higher rates of major affective disorders, eating disorders, and alcoholism in first-degree relatives of 40 bulimic probands than in first-degree relatives of 24 control subjects. More importantly, the data showed higher rates of major affective disorders in relatives of bulimic probands who themselves had no history of major affective disorders than in relatives of control subjects. This significant finding indicates a familial relationship between bulimia nervosa and major affective disorders, which suggests the possibility of a common diathesis.

Clinical features of illness in siblings with schizophrenia or schizoaffective disorder.

Evidence implicating genetic or prenatal-perinatal environmental causes in the familial aggregation of schizophrenia led us to study 53 sets of siblings, two or more of whom had chronic psychosis, either schizophrenia or schizoaffective disorder. We looked for similarities in clinical features and concordance of diagnosis within sibships to test for shared familial causes. Clinical variables, including diagnosis, specific symptoms, age at onset, and nongenetic perinatal factors, were studied. Auditory hallucinations, paranoid delusions, thought disorder, negative symptoms, and poor premorbid social adjustment did not significantly correlate in siblings. Concordance was found for schizoaffective disorder and history of major depressive episodes, suggesting that schizophrenia with a depressive component and Research Diagnostic Criteria schizoaffective illness may represent a specific etiologic subtype(s) of the illness, whereas the other noted symptoms may represent the variable expression of the disorder. Age at onset and at first hospitalization were significantly correlated, consistent with genetic or other familial factors on time of onset. Birth complications were significantly more frequent among the schizophrenic compared with non-psychotic siblings, had a familial component, and tended to be associated with an earlier age at onset. Thus, nongenetic perinatal factors may increase the risk for schizophrenia in a familial form of the illness and contribute to the correlation of ages at onset in siblings.