Clinical methods in psychiatric genetics. II. The high risk approach.

The study of individuals at "high" risk for developing psychiatric disorders is useful in confirming that a biological trait marker identified in patient populations is also present in genetically susceptible individuals who have never been ill, and predicts the future onset of illness. We outline a systematic method for deciding which variables to choose and how many individuals are required in order for a study to have sufficient power. We demonstrate how these decisions depend on the assumptions that can be made with regard to the mode of inheritance of the biological trait, the relationship of the biological trait to illness, and the magnitude of the mean difference observed between patients and controls.

Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies.

Population stratification, secondary effects of illness or treatment, biological heterogeneity of a clinical syndrome, or complex biology underlying a syndrome (where only one component is measured) are conditions which may obscure the association of a genetic risk factor with a clinical syndrome. We consider several investigative strategies under each of these conditions. Only segregation-based paradigms are robust to genetic heterogeneity and population stratification.

A family study of the association of increased ventricular size with schizophrenia.

Families with more than one individual of the same generation with the diagnosis of schizophrenia were recruited for studies. Brain lateral ventricular size was quantified in 26 schizophrenic subjects from 12 unrelated families, their available well siblings (N = 10), and 20 nonpsychotic controls. Lateral ventricular size was significantly greater in the schizophrenics than in their well siblings and controls.

Pro-opiomelanocortin-related peptides in cerebrospinal fluid: a study of manic-depressive disorder.

Five peptide fragments of pro-opiomelanocortin (alpha-melanocyte-stimulating hormone, beta-lipoprotin, adrenocorticotropic hormone, beta-endorphin, and the N-terminal fragment of pro-opiomelanocortin) were measured by radioimmunoassay in cerebrospinal fluid (CSF) and plasma from 31 normal volunteers and 26 euthymic lithium-treated bipolar patients (14 of whom provided a second CSF sample in the unmedicated state). With the exception of alpha-melanocyte-stimulating hormone, in the normal volunteers' CSF, levels of these peptides were highly correlated with one another, suggesting that: (1) some common regulatory factor may control the levels of these four peptides in CSF; and (2) CSF alpha-melanocyte-stimulating hormone is independently regulated from the other pro-opiomelanocortin products. Some of these correlations were absent in the patient groups, suggesting subtle alterations in pro-opiomelanocortin processing in manic-depressive illness.

Hereditary malignant melanoma is not linked to the HLA complex on chromosome 6.

Detailed HLA typing was performed in 11 families with hereditary cutaneous malignant melanoma (CMM) and dysplastic nevi to determine if the melanoma susceptibility locus was genetically linked to the major histocompatibility complex. Previously published data from 19 other families were re-analyzed in the same manner. When data from all 30 families were pooled and CMM was defined as the disease trait, the hypothesis of linkage was rejected for all values of recombination (theta) less than 40%.

Neuropeptides in human cerebrospinal fluid.

Ten neuropeptides were measured by RIA in human cerebrospinal fluid obtained from 30 normal volunteers. The levels of seven peptides (corticotropin releasing factor, adrenocorticotropin, vasoactive intestinal peptide, somatostatin, beta-endorphin, beta-lipotropin, and the N-terminal fragment of proopiomelanocortin) were highly, positively correlated with one another. This result is consistent with the hypothesis that cerebrospinal fluid levels of these seven peptides are a function of some common regulatory factor, such as shared release into the cerebrospinal fluid.

Twenty-seven protein polymorphisms by two-dimensional electrophoresis of serum, erythrocytes, and fibroblasts in two pedigrees.

Twenty-seven independent polymorphic loci were detected by two-dimensional electrophoresis (2DE) of serum, erythrocytes, and fibroblasts in two large families and analyzed for linkage to classical genetic markers. We detected seven serum, four erythrocyte, and 17 fibroblast protein loci that exhibited charge variation in these two families and in a sample of unrelated individuals. The genetic basis of protein variants was confirmed by quantitative gene-dosage dependence and by conformance to Mendelian transmission in the two families, except for four rare variants for which transmission analysis was not possible.

Multiple threshold models for the affective disorders: the Yale-NIMH collaborative family study.

From the Yale-NIMH collaborative family study, the 1482 first degree relatives of 90 bipolar 1, and 163 major depression probands were examined to test the hypothesis that bipolar 1 and major depression are due to a single underlying genetic liability. We attempted to fit multifactorial-polygenic and single-major-locus multiple threshold models for sex and severity to the relatives in the major depression and bipolar 1 families. With relatives classified as affected only if they met criteria for major depression or bipolar 1, there was at best only marginal support for these models.

Segregation analysis of dopamine-beta-hydroxylase (DBH) and catechol-O-methyltransferase (COMT): identification of major locus and polygenic components.

Enzymes of catecholamine metabolism, plasma dopamine-beta-hydroxylase (DBH), and erythrocyte catechol-O-methyltransferase (COMT) were each previously shown to be transmitted as single codominant loci in a sample of approximately 30 multigenerational families that were analyzed with the single major locus model. Here, both major locus and polygenic hypotheses are tested by applying the mixed model of analysis to the identical samples, after breaking the families into two-generation units. For plasma DBH, the most parsimonious model is a dominant major locus (ie, high values dominant to low values) accounting for 41% of the variance and a polygenic component accounting for 25% of the variance.

Heritability of forskolin and hormone-stimulated adenylate cyclase activity in human lymphocytes.

Isoproterenol, prostaglandin E1 and forskolin-stimulated cyclic AMP accumulation were compared in intact lymphocytes obtained from nine monozygotic and nine sib pairs matched for age and sex. Heritability was calculated by three different methods, two based on the intraclass correlation coefficients and one based directly on the variances. Only for forskolin is a significant proportion of variance (0.

Linkage between X-chromosome markers and manic-depressive illness. Two Sardinian pedigrees.

Pedigrees of manic-depressive patients in treatment at the Lithium Clinic of the Institute of Clinical Pharmacology, University of Cagliari, were evaluated for linkage between major affective illness and the protan-deutan-glucose-6-phosphate-dehydrogenase region of the X-chromosome. Two informative pedigrees were found, investigated and analyzed for linkage using a multigenerational model and considering age-dependent penetrance. The results are consistent with the hypothesis of X-linkage in major affective illness.

Platelet monoamine oxidase (MAO) activity: evidence for a single major locus.

Monoamine oxidase (MAO), a mitochondrial enzyme involved in the degradation of biogenic amines, has been associated with psychiatric morbidity. Although twin and family studies have indicated that MAO activity is familial, the exact mode of transmission is unclear. We performed segregation analysis on 154 nuclear families containing 419 individuals using the mixed model, which allows for a single major locus with a polygenic background.

The detection of major loci by segregation and linkage analysis: a simulation study.

Simulated multigenerational pedigrees were analyzed using the program GENPED and POINTER to examine the 1) limits of segregation analysis for detecting single locus, two-allele transmission of a dichotomous trait and 2) accuracy of the parameter estimates. Ten data sets of 30 pedigrees each (approximately 25 persons per pedigree) were simulated. The genotypic penetrance values were varied but the population prevalence of the trait was kept constant at 2%.

Genetic factors in affective illness.

Research strategies for determining genetic vulnerability markers in affective illness are delineated. Using these strategies, recent developments in the biology of manic-depressive illness are discussed, including results from association and linkage studies, pharmacologic challenge protocols, and cerebrospinal fluid (CSF) data. Several lines of evidence suggest that one genetically determined vulnerability to affective disorder may be a cholinergic supersensitivity, possibly mediated through increased numbers of cholinergic receptors.

Familial cutaneous malignant melanoma: autosomal dominant trait possibly linked to the Rh locus.

Segregation and linkage analyses were undertaken in families with multiple cases of cutaneous malignant melanoma (CMM) and a recently-described melanoma precursor, the dysplastic nevus syndrome (DNS). Clinical and laboratory data, including 23 genetic markers, were collected on 401 members of 14 high-risk kindreds. Pedigree analysis was compatible with an autosomal dominant mode of inheritance for the familial CMM trait.

Segregation and linkage analyses in families of patients with bipolar, unipolar, and schizoaffective mood disorders.

Hypotheses of single major locus transmission (autosomal and X chromosome) of major affective disorder (i.e., bipolar, unipolar, and schizoaffective) are tested using the Elston-Stewart likelihood method of pedigree segregation analysis.

Association and linkage studies of genetic marker loci in major psychiatric disorders.

Studies of the segregation of major psychiatric disorders in families are consistent with multiple threshold polygenic models rather than with major locus transmission. This does not however rule out the possibility of identifying major locus traits that correlate with disease susceptibility. One approach has been to ascertain the degree of association between well characterized genetic markers and psychiatric disorders.

A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands.

In a family study of 1,254 adult relatives of patients and controls, lifetime prevalences of major affective disorder (including schizoaffective) were 37%, 24%, 25%, 20% and 7% in relatives of probands with schizoaffective, bipolar I, bipolar II, and unipolar disease, and normal controls. These data were compatible with the different affective disorders representing thresholds on a continuum of underlying multifactorial vulnerability. In this model, schizoaffective illness represents greatest vulnerability, followed by bipolar I and bipolar II, then unipolar illnesses.

Relationship of HLA to major affective disorder not supported.

A recently published report (Weitkamp et al., 1981) concludes that a major susceptibility locus for depression is located in the HLA region of chromosome 6. This conclusion was based on increased sharing of HLA haplotypes in affected sib pairs and nonrandom segregation of HLA types and illness in families.

Segregation and linkage studies of plasma dopamine-beta-hydroxylase (DBH), erythrocyte catechol-O-methyltransferase (COMT), and platelet monoamine oxidase (MAO): possible linkage between the ABO locus and a gene controlling DBH activity.

Measurements of dopamine-beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase (MAO) along with 27 polymorphic marker phenotypes were available for 162 patients with major affective disorders and 1,125 of their relatives. Levels of enzymes were previously found not to be associated with illness. Pedigree analysis methods for quantitative traits are used to test single-gene hypotheses for segregation of DBH in 32 families with 411 individuals.