Sibling pairs with affective disorders: resemblance of demographic and clinical features

O’Mahony, Edmond; Corvin, Aiden; O’Connell, R.M.; Comerford, Claire; Larsen, Bo; Jones, Ian; McCandless, F.; Kirov, George; Cardno, Alastair G.; Craddock, Nicholas John; Gill, M.

doi:10.1017/s0033291701004986

Cited by 54 publications

(35 citation statements)

References 26 publications

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“…About 58% of manias include delusions and/or hallucinations, 36 and these features tend to aggregate in certain BP families. 10,11,37 Such observations have motivated several studies to examine linkage in BP with psychosis. Our group previously carried out a stratified linkage analysis of BP families loaded with relatives having psychotic symptoms and found significantly increased evidence of linkage in two regions on chromosomes 13q31 and 22q12.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

et al. 2007

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Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a nonparametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.

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Section: Discussionmentioning

confidence: 99%

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

et al. 2007

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“…55,56 Similarly, Schurhoff et al 57 found a familial aggregation of proneness to delusions in a combined sample of families of schizophrenic and bipolar probands and O'Mahony et al 58 found correlation of 'psychotic dimension' in an analysis of affected sib pairs from 160 families of bipolar probands. Using the presence of psychotic symptoms during affective episodes as a means to stratify linkage results, positive lod scores on 13q31 (region containing the locus G72/G30) and 22q12 were obtained from a subset of 10 families with three or more members with a history of psychotic symptoms.…”

Section: Psychotic Symptoms In Bdmentioning

confidence: 97%

“…A modest correlation in frequency of episodes among affected siblings has been observed. 58 In a study of children of bipolar parents, Duffy et al 116 found a strong association between the quality of remission in affected parents and children.…”

Section: Clinical Course and Outcomementioning

confidence: 99%

“…Affected relatives appear to have similar onset. 58 Bellivier et al 106 analysed the distribution of age of onset and concluded that age of onset was correlated in affected family members. When Faraone et al 107 investigated age of onset as a quantitative trait in linkage analysis of BD, they found that the onset of mania was heritable (h 2 ¼ 0.41) and using it as a phenotype provided suggestive lod scores on chromosomes 12p, 14q, and 15q, in regions not implicated by traditional linkage analyses of that or other data sets.…”

Section: Clinical Course and Outcomementioning

confidence: 99%

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The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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“…AAO in both schizophrenia and major affective disorders (e. g., bipolar disorder) varies considerably, spanning several decades. AAO has been proposed as a possible marker of etiologic and genetic heterogeneity [10,27]. Some studies have reported an association between early onset schizophrenia and an increased risk of schizophrenia in relatives [1,2,20,26,32,33,35], suggesting that the early form of illness may have a higher familial liability to schizophrenia than later onset forms.…”

Section: Introductionmentioning

confidence: 99%

Heritability of schizophrenia and major affective disorder as a function of age, in the presence of strong cohort effects

Husted

Greenwood

Bassett

2005

Eur Arch Psychiatry Clin Neurosci

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It remains unclear whether age at onset for major psychiatric disorders is a useful marker of etiologic and genetic heterogeneity. The authors examined how heritability of schizophrenia and major affective disorders varied with age at onset. The sample was drawn from a large archival data set collected by Lionel Penrose, comprising 3,109 families with two or more members first hospitalized in Ontario between 1874 and 1944. The authors studied 1,295 sibships with schizophrenia (n = 487), major affective disorder (n = 378), both (n = 234) or neither (n = 196) of these disorders. Proportional hazards models were used to estimate how the hazard of hospitalization for each disorder (schizophrenia or major affective disorder) varied with proband age at onset, adjusted for changes in age at onset distribution between 1874 and 1944. A sibling's risk of hospitalization for the same illness significantly increased for each 10-year decrease in age at onset of the proband both for schizophrenia (hazard ratio = 1.21, 95 % confidence interval: 1.06, 1.39), and for affective disorder (hazard ratio = 1.29, 95 % CI: 1.14,1.45). Gender of proband was unrelated to sibling risk of the same illness, and tests of interaction effects between proband age at onset and gender on sibling risk were nonsignificant.

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Sibling pairs with affective disorders: resemblance of demographic and clinical features

Abstract: Significant but modest familial resemblance has been shown for some specific features of bipolar illness, particularly age at onset and degree of psychosis. Further research may establish the extent to which these findings are mediated by genetic and/or environmental factors.

Cited by 54 publications

References 26 publications

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

The phenotypes of bipolar disorder: relevance for genetic investigations

Heritability of schizophrenia and major affective disorder as a function of age, in the presence of strong cohort effects

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