Jürgen Minges

Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families.

Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined (‘either’ families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22–23 in the ‘either’ families. The findings on 18p11.2 and 18q22–23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of ‘either’ families requires further study.

Personality traits in subjects at risk for unipolar major depression : a family study perspective

Particular patterns of personality (e.g., introversion, neuroticism, obsessionality) have been found to be associated with unipolar depression by a large number of investigators; recent prospective studies have stressed neuroticism as a premorbid risk factor for depression. This study examines whether similar patterns of personality are found in relatives of affective disorder patients and of controls. First-degree relatives of normal controls and of subjects with primary unipolar depression were studied using the Munich Personality Test. Relatives in remission from an episode of unipolar depression had clearly higher levels of neuroticism and rigidity and lower levels of extraversion than controls; healthy relatives of controls had higher levels of rigidity (both sexes) and of neuroticism (males only) than controls. It is proposed that these traits are either risk factors for depression or attenuated forms of depression.

The reliability of the SADS-LA in a family study setting.

SummaryThe joint-rater and test-retest reliability study of two translated versions of the SADS-LA (Schedule for Affective Disorders and Schizophrenia-Lifetime version — modified for the study of anxiety disorders), one in French and the other in German, have been tested in family study settings, in a sample of patients and firstdegree relatives. The test-retest reliability study demonstrated that identification of major affective disorders and schizophrenia was performed with sufficient reliability; however, diagnoses of subtypes of major disorders (e.g. bipolar II disorder) and identification of minor disorders was cless reliable. The implications of these findings in phenotype identification during family studies in psychiatry are discussed.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25-q26

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25–q26. The highest two-point LOD score (2.86, θ = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25–q26.

The familial relationship between panic disorder and unipolar depression

This controlled family study explores (1) whether panic disorder and unipolar depression share familial factors, and (2) whether the co-occurrence of lifetime diagnoses of panic disorder and unipolar depression in individuals defines a distinct diagnostic subtype in terms of familial aggregation. To be most informative, the familial lifetime prevalence rates for panic disorder and unipolar depression have to be determined in a set of four proband groups: 78 patients with unipolar depression and panic disorder. 121 patients with unipolar depression alone (no panic disorder), 81 patients with panic disorder alone (no unipolar depression), and 109 control probands sampled in the general population were compared by lifetime prevalence rates for panic disorder and unipolar depression in their first-degree relatives. Altogether 1046 relatives were interviewed directly; family history information was available on another 346 subjects. Both disorders were aggregating in families. We found modest overlap of familial components; the relative risk of panic disorder only in relatives of patients with unipolar depression only was 2.3, and the relative risk of unipolar depression only in relatives of patients with panic disorder only was 1.8. The comorbid condition did not represent a distinct subtype in terms of familial aggregation. Excess comorbidity was observed in affected relatives independent of the diagnostic status of the index case. Thus, a sharing of familial factors of aetiological relevance between panic disorder and unipolar depression might explain a limited proportion of comorbid cases. However, the major proportion of comorbidity between panic disorder and unipolar depression may still be due to non-familial factors.

Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene.

We report two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene. The two polymorphisms are characterized by single base pair substitutions, namely a G→C transversion changing codon 11 from GGG (encoding Gly) to CGG (encoding Arg) and a C→T transition in position −11 upstream from the start codon. The Arg11 variant occurs at a frequency of about 1% and the C→T transition at a frequency of about 7% in German control subjects (n = 148). Allele frequencies observed in patients suffering from schizophrenia (n = 256) and bipolar affective disorder (n = 99) were similar. The deletion variant is characterized by a 21 bp deletion affecting codons 36 to 42 coding for amino acids Ala-Ala-Leu-Val-Gly-Gly-Val located in the first transmembrane domain of the dopamine D4 receptor. The mutation was identified in a single individual suffering from obsessive-compulsive disorder and panic disorder. We were unable to detect the deletion in patients with schizophrenia and bipolar affective disorder, nor in healthy controls.

Unipolar depression in the aged: determinants of familial aggregation.

Late-onset depression (greater than or equal to 60 years) is believed to be less associated with a risk of depression in first-degree relatives than early-onset depression. However, family studies in elderly probands fitting the current methodological standards of family studies are not available. The reported family study in geriatric inpatients with unipolar major depression (n = 92) supported the proposed relationship between age at onset and the proposed familial loading. A comparison to families of age-matched controls (n = 33) revealed that relatives of probands with late-onset depression are still at an increased risk of depression. However, late-onset depression was not more common in families of probands with late-onset depression than in families of probands with early-onset depression. Besides the age at onset, the recurrence of depressive episodes defined distinct patterns of familial aggregation.

The relationship between alcoholism and unipolar depression—A controlled family study

This family study explores the controversial relationship between unipolar major depression and alcoholism. Thirty-nine families of patients with non-psychotic unipolar depression and alcoholism, 160 families of patients with non-psychotic unipolar depression without alcoholism, and 64 families of patients with alcoholism without psychotic or major affective disorders were compared with 109 families of unscreened probands recruited in the general population. Both disorders were familial. They were transmitted independently in families; a sharing of substantial genetic or of other familial components between the two disorders was unlikely to occur in the sample under study, particularly among male subjects. Comorbidity between the two disorders was more common than expected by chance, but excess comorbidity was preferentially mediated by non-familial factors. Reasons for discrepancies among the conclusions of different family studies on these issues are discussed.

The risk of minor depression in families of probands with major depression: Sex differences and familiality

SummaryCurrently it is not clear whether minor forms of unipolar depression not matching the criteria of “major depression” should be considered as a separate diagnostic category. A controlled family study examined the familial aggregation of minor depression among probands with unipolar major depression. In the families of these probands the relative risk for minor depression was elevated by a similar magnitude to the risk for major depression. Threrefore, the diagnostic category “minor depression” would not increase diagnostic sensitivity at the expense of diagnostic specificity as far as familiality is the criterion. In agreement with recent epidemiological studies, minor depression did not reveal a similar excess prevalence in females compared with males as major depression does. The variation of the sex ratio for any subtype of unipolar depression was not associated with the familiality of this disorder.

Alcoholism and panic disorder : co-occurrence and co-transmission in families

SummaryThe co-occurrence of alcoholism and anxiety disorders in epidemiological and clinical samples is well established. Self-medication of anxiety disorder probands with the anxiolytic substance alcohol might be one reason for this association. Common susceptibility factors of both disorders might be alternative explanations. Controlled family studies recruiting probands with panic disorder and alcoholism are powerful tools to answer this question. A family study of this kind, however, is not available. The present study investigated 113 families of probands with either panic disorder or alcoholism or both (but without affective or psychotic disorders) and 80 families of healthy controls in order to estimate the degree of co-occurrence of the two disorders in nontreated samples of relatives and to explore the magnitude of overlap between susceptibility factors of the two disorders. The co-occurrence of the two disorders was relatively rare in all samples of families under study. Overlap of susceptibility factors was demonstrated by an elevated risk of alcoholism in relatives of probands with panic disorder.