Heritability and familiality of psychopathologic dimensions in Korean families with schizophrenia

Abstract

Aim:

Categorical syndromes such as schizophrenia could be a combination of many continuous mental structure phenotypes including several personality development/degeneration dimensions. This study investigated the heritability and familiality of symptom check list (SCL) psychopathologic dimensions in Korean schizophrenia linkage disequilibrium families.

Method:

We recruited 204 probands (with schizophrenia) with their parents and siblings whenever possible. We used the SCL questionnaire to measure psychopathologic dimensions. The heritability of symptomatic dimensions in 543 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Psychopathologic dimensions in the 543 family members were compared with those in 307 healthy unrelated controls to measure familiality on using analysis of variance (ANOVA) analysis.

Results:

Five of the nine SCL variables were significantly heritable and were included in the subsequent analyses. The three groups (control, unaffected first-degree relative, schizophrenia patient) were found to be significantly different with regard to the expected order of average group scores for all heritable dimensions.

Conclusion:

Aberrations in several symptomatic dimensions could contribute to the complexity of schizophrenia syndrome as a result of genetic–environment coaction or interaction in spite of some limitations (recruited family, phenotyping).

Schizophrenia is the most devastating mental illness, and it can lead to deterioration in the social and occupational functioning of affected individuals,^1,2 with a major cost to society.^3,4 A wide range of studies suggests a genetic component to the inheritance of this disorder.⁵ Although family, twin, and adoption studies have provided strong evidence that genetic variation plays a major role in the etiology of schizophrenia, susceptibility genes have proven difficult to identify definitively.

Many researchers in neuroscience are devoting their work to elucidate the causes of schizophrenia, especially in basic genetics fields. Its mystery, however, is in line with the mystery of the brain. Advances in the understanding of this disorder are few compared with the effort put in. Even a recent study performed in a large and heter-ogenous sample of European ancestry was discouraging because it indicated that 14 genes previously consistently identified as contributing to susceptibility to schizophrenia might play only a small role.⁶ This is probably due to various factors, including genetic and environmental factors associated with the expression of schizophrenia, along with genetic heterogeneity and the polygenic inheritance of schizophrenia.

More work, at both the population and molecular levels, however, needs to be done before dismissing these genes and their connection to schizophrenia. Many studies suggest that variation in phenotypes should be investigated. One way to investigate the fundamental pathology of this complex disease is to use a phenotype. It is very clear that there are limitations in categorical phenotypes, such as the DSM-IV system. Many researchers are exploring comparable quantitative endophenotypes alternative to classical qualitative phenotypes that represent schizophrenia. Gottesman and Gould have suggested that useful endophenotypes must be reliable, stable, and heritable.⁷

Mode-of-inheritance studies have suggested that multiple genes are likely to be involved in the etiology of schizophrenia. If the effect of any single gene is generally modest for schizophrenia, the clinical features that tag more genetically homogeneous subtypes could be identified, thus facilitating susceptibility gene identification. Clinical subtyping has been an effective method in determining the etiology of other illnesses such as Alzheimer’s disease and breast cancer, in which families with early onset illness have led researchers to the identification of disease-related genes.^8,9

Several clinical features have been shown to increase the evidence of genetic linkage to chromosomal regions or association with gene variants. Comorbid panic disorder¹⁰ and bipolar II disorder¹¹ appear to enhance linkage with distinct regions on chromosome 18q. In two datasets, psychotic features showed linkage to chromosome 13q,^12,13 and early age at onset showed linkage to chromosome 21q22 in two cohorts. It has been reported that mania at onset enhanced linkage to chromosome 16p; and a linkage to chromosome 2 was shown to be associated with attempted suicide in bipolar disorder.¹⁴ Psychotic features, mood-incongruent psychotic features, and persecutory delusions in bipolar disorder have strengthened the evidence suggesting a genetic association with DTNBP1 (dysbindin), NRG1 (neuregulin), and DAOA (G72), respectively.¹⁵ These early successes suggest that clinical phenomenology can help define more genetically homogenous forms of schizophrenia.

The choice of features studied in schizophrenia genetics has been largely guided by clinical experience. Features that show familial aggregation may be particularly promising,¹⁶ and most of these features, which enhance linkage or association signals, are indeed familial, as mentioned previously. Only a minority of the myriad of clinical features in schizophrenia, however, have been studied.

The study of clinical features has been limited by the time-consuming process of gathering and assembling relevant clinical data in cohorts of sufficient size. Large-scale genetics efforts have yielded the human genome sequence and, more recently, the HapMap, a reference catalogue of common human sequence variants. The authors of the HapMap study called for similar large-scale efforts in the phenotypic arena. A similar concept, the ‘Human Phenome Project’, was advanced by Freimer and Sabatti.¹⁷ Freimer and Sabatti advocated an international effort to create phenomic databases: comprehensive assemblages of systematically collected phenotypic information, to aid the identification of disease genes.¹⁷ In this vein, the Autism Phenome Project has implemented a prospective compilation of comprehensive phenotypic data in order to parse the genetic heterogeneity in autism,¹⁸ and an Epilepsy Phenome-Genome Project is planning similar work (http://65.175.48.5/epgp/index.htm). The aforementioned study for establishing the Bipolar Disorder Phenome Database could be applied to establishing a Korean Schizophrenia Phenome Database. To our knowledge, no comparable databases for schizophrenia exist as yet.

One possible mechanism responsible for this syndrome may be the manifestation of genetic aberrations in mental dimensions as sub(endo)phenotypes. Categorical syndromes such as schizophrenia could be a complex of many continuous mental structure phenotypes, including several personality development/degeneration dimensions. Quantitative endophenotypes are essential to better understand the pathogenesis of schizophrenia. This concept was reflected in a recent publication on DSM-5 through the schizophrenia spectrum and other psychotic disorders.

Many models suggest that psychopathologic dimensions including personality are heritable and influence the genetic loading of schizophrenia. Personality traits are under genetic influences, and the heritability of personality reaches 30–60%. Personality has high familial tendencies in the general population and in various psychiatric disorders including major depression, alcohol dependence, and bulimia. Besides neuropsychologic or neurobiologic characteristics, the biogenetic components of personality may also be considered as an endophenotype of schizophrenia, if they could be found in both schizophrenia probands and their first-degree relatives.^19–23

The symptom check list-90-revised version (SCL-90-R) is a representative screening tool for diagnosing and differentiating schizophrenia from other mental disorders. Comparison of four groups of substance-abusing inpatients with different psychiatric comorbidities including schizophrenia was performed using this questionnaire.²⁴ The psychoticism dimension of the SCL-90-R was the most important predictor of hallucination-like experiences in the analysis of the multidimensionality of hallucination-like experiences in clinical and nonclinical Spanish samples.²⁵ The primary study outcome was a change in subjective symptoms measured by the SCL-90-R from baseline, in the clinical trial for assessing the effectiveness of paliperidone extended-release for patients with schizophrenia. The psychiatric symptoms were assessed with a semi-structured interview and the SCL-90-R in the reappraisal of interplay between psychosis and depression symptoms in the pathogenesis of psychotic syndromes. Two psychosis syndromes derived from the SCL-90-R, were applied: ‘schizotypal signs’ and ‘schizophrenia nuclear symptoms’, for analyzing the subclinical psychosis syndromes in the general population.^24–27

The psychobiological model of personality suggests that an individual’s temperament is heritable and is regulated by neurotransmission linked to the pathophysiology of schizophrenia. More recently, evidence suggested that dimensions of character are also heritable, and may influence the risk of schizotypy. Harm avoidance has been suggested for genetic loading in previous studies, although some of them have produced conflicting results.^28–34 This study was therefore conducted to investigate the heritability and familiality of SCL psychopathologic dimensions in Korean families with schizophrenia.

Methods

We recruited 204 probands (with schizophrenia) along with their parents and siblings whenever possible. For the best estimation of diagnosis, we used medical records and a Korean version of Diagnostic Interview for Genetic Studies (DIGS) and Family Interview for Genetic Studies (FIGS). We also used the SCL questionnaire to measure the psychopathologic dimensions.

The SCL-90-R is a self-report multidimensional symptom checklist questionnaire consisting of nine basic symptom dimensions and three general dimensions measuring the overall psychopathologic levels. We used the Korean version that consists of 90 questions, standardized by Kim et al.³⁵

Sample collection

All subjects were recruited and gave informed consent in accordance with the principles of the Declaration of Helsinki and with approval from the Institutional Review Boards of the Pusan National University Hospital. Probands were recruited independently from the Pusan National University Hospital. All probands had disease onset by age 40, a history of at least one psychiatric hospitalization, a discharge diagnosis of schizophrenia, and Korean surnames. Most patients with schizophrenia typically develop psychotic symptoms by at least their late 20s. We recruited probands with disease onset by age 40 to reflect the clinical points to include core schizophrenic probands. Subjects with potentially biasing conditions (pre-existing organic mental disorders, alcohol use disorders, substance abuse, and personality disorders) were excluded from the study. Parents and first-degree relatives of probands were also recruited wherever possible to permit determination of genetic phase and to allow for family-based linkage disequilibrium (LD) analyses. If additional relatives with psychotic disorders were detected, efforts were made to recruit these relatives as well, but no affected relatives could be recruited. Each subject was interviewed by a trained Korean psychiatrist who was blinded to the previous history of the subject, using the Korean version of the DIGS.³⁶ Medical records (inpatient and outpatient) were also abstracted. An interview with a close relative, using a Korean version of the FIGS, was also completed for each subject.³⁷ In total, 204 probands and their available family members were analyzed in the current study (Table 1). All affected subjects (i.e. those given formal psychiatric diagnoses for the present study) in each family were diagnosed using a best estimate diagnostic process, as described by Walss-Bass et al.³⁸ The process arrives at a lifetime consensus diagnosis or diagnosis using the DSM-IV. The number of subjects and families analyzed in this paper were as follows: 543 subjects from 204 families. The 204 probands had axis I disorders by consensus DSM-IV diagnosis with schizophrenia, and 339 other family members including first-degree relatives who had no axis I disorders were selected.

Table 1.

Demographic characteristics at recruitment

	No. subjects	Age (years)		Sex
		Mean ± SD/SEM	Mean ± SD/SEM	Male n(%)/Female n (%)	Male n(%)/Female n (%)
Pedigree members	543	44.3 ± 15.8/0.7		255 (47.0)/288 (53.0)
Probands with schizophrenia	204		35.0 ± 11.8/0.8		102 (50.0)/102 (50.0)
Unaffected first-degree relatives	339		50.3 ± 15.2/0.9		153 (45.1)/186 (54.9)
Control members	307
Unrelated subjects	307	28.7 ± 2.9/0.2	28.7 ± 2.9/0.2	159 (51.8)/148 (48.2)	159 (51.8)/148 (48.2)
Statistics	NA	t = 14.6	F = 242.1	χ2 = 1.8	χ2 = 3.0
P-value		<0.001	<0.001	0.2	0.2

NA, not applicable.

In total, 204 subjects had a history of psychosis, operationalized in this study as the presence of at least one of the following at some point during their lifetime: hallucinations, delusions, grossly disorganized thought processes, or grossly disorganized behavior. This definition of psychosis corresponds to four of the five symptoms and signs listed under criteria A of the DSM-IV definition of schizophrenia. We did not consider a history of ‘negative symptoms’ (abulia, alogia, avolition), also listed under criteria A of the DSM-IV definition of schizophrenia, as sufficient for a diagnosis of psychosis. For each subject the best estimators also diagnosed whether or not manic syndromes or episodes had been present during the course of the disorder. Distinction between schizophrenia and schizoaffective disorder followed the DSM-IV criteria, as operationalized in Walss-Bass et al.³⁸

The present study included 307 Korean control subjects who were psychiatrically normal but who did not belong to the age groups specified in the pedigree sample, the limitations of which will also be discussed. Subjects with potentially biasing conditions were excluded from the study. Subjects were also excluded if they had been receiving corticoid, estrogen, androgen, or triiodothyronine (T3)–thyroxine (T4) therapy or diphenylhydantoin, vitamin D, bisphosphonate, calcitonin, fluoride, thiazide diuretics, or barbiturates for >6 months, given that all these drugs may yield biasing effects, because it was impossible to obtain a population-based register for technical and legal reasons, control subjects meeting the inclusion/exclusion criteria were identified from volunteers (students and hospital workers) at the hospital.

Statistical analysis

Heritability of personality dimensions in the total 543 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR).^39,40 SOLAR is an extensive, flexible software package for genetic variance components analysis, including linkage analysis, quantitative genetic analysis, single-nucleotide polymorphisms (SNP) association analysis (QTN, QTLD, and MGA), and covariate screening. Operations are included for the calculation of marker-specific or multipoint identity-by-descent (IBD) matrices in pedigrees of arbitrary size and complexity, and for linkage analysis of multiple quantitative traits and/or discrete traits that may involve multiple loci (oligogenic analysis), dominance effects, household effects, and interactions. Heritability represents the portion of phenotypic variance accounted for by the total additive genetic variance. Genetic variance is the portion of phenotypic variance due to pedigree relationships rather than environmental factors or errors. Indices with stronger covariance between genetically more similar individuals rather than between genetically less similar individuals have higher heritability. In the SOLAR program, this is assessed by contrasting the observed covariance matrices for a trait with the covariance matrix predicted by kinship. Personality dimensions in total family members were compared with those in 307 healthy unrelated controls for measuring the familiality using ANOVA in SPSS, version 11.5 (SPSS, Chicago, IL, USA). Genetic/environmental correlations with symptomatic dimensions for significant psychopathologic dimensions aggregated in families were also investigated using SOLAR. The significance level required was 5%.

Results

Heritability

Five of the nine SCL variables were significantly heritable and were included in subsequent analyses. Heritability was the highest for interpersonal sensitivity (0.59, P = 0.001) and the lowest for phobia (0.38, P = 0.03). Four SCL variables (Somatization, Anxiety, Paranoia, Psychoticism) were not significantly heritable and were excluded from subsequent analyses (Table 2).

Table 2.

Heritability of SCL psychopathologic measures

Symptomatic dimensions	H2r	H2r (SE)	P-value	Significant covariates
Somatization	0.13	0.19	0.25	Sex
Obsessive–Compulsive	0.52	0.20	0.01*	Age
Interpersonal–Sensitivity	0.59	0.17	0.001*	Sex, Age, Age2 × Sex
Depression	0.52	0.17	0.002*	Sex
Anxiety	0.22	0.17	0.09	Sex
Hostility	0.42	0.20	0.03*	NA
Phobia	0.38	0.19	0.03*	Sex, Age
Paranoia	0.24	0.18	0.09	NA
Psychoticism	0.15	0.17	0.19	Sex

^*P < 0.05.

H2r, heritability; NA, not applicable; SCL, symptom check list; SE, standard error.

Familial aggregation

The control, unaffected first-degree relative, and schizophrenia patient groups were significantly different and showed the expected order of average group scores for all heritable dimensions. Five heritable dimensions (high obsessive–compulsive, high interpersonal-sensitivity, high depression, high hostility, high phobia) could qualitatively differentiate the schizophrenia patient group from the first-degree relatives and control group (P < 0.05; Table 3).

Table 3.

Familial aggregation of psychopathologic measures: SCL t score

Symptomatic dimensions	Control Mean ± SD	Unaffected first-degree relative Mean ± SD	Schizophrenia probands Mean ± SD	P-value	P-value adjusted for age
Obsessive–Compulsive	40.5 ± 7.2	43.6 ± 8.2*	51.0 ± 13.3*,†	<0.001	0.000
Interpersonal–Sensitivity	43.1 ± 7.3	44.9 ± 8.5*	53.3 ± 14.4*,†	<0.001	0.000
Depression	40.6 ± 6.0	45.1 ± 9.0*	51.4 ± 13.1*,†	<0.001	0.000
Hostility	42.2 ± 4.9	45.0 ± 7.3*	49.1 ± 11.8*,†	<0.001	0.000
Phobia	43.3 ± 5.3	46.4 ± 23.7*	55.9 ± 15.9*,†	<0.001	0.000

^*P < 0.05 vs controls by Scheffe test.

^†P < 0.05 vs first-degree relatives by Scheffe test.

SCL, symptom check list; t score, in psychometrics, a t score is a type of standard score computed by multiplying a z-score by 10 and adding 50.

Genetic/environmental correlation

Genetic/environmental correlation with schizophrenic phenotype for psychopathologic dimensions aggregated in families was suggested (Table 4).

Table 4.

Bivariate analysis between affection status and psychopathologic measures

SCL symptomatic dimensions	Schizophrenia phenotype
	Genetic correlation		Environmental correlation
	ρg (SE)	P-value	ρe (SE)	P-value
Obsessive–Compulsive	0.59 (0.71)	0.40	0.23 (0.35)	0.54
Interpersonal–Sensitivity	−0.04 (0.68)	0.96	0.68 (0.28)	0.04
Depression	0.58 (0.67)	0.35	0.14 (0.42)	0.75
Hostility	0.66 (0.73)	0.34	−0.0009 (0.48)	0.99
Phobia	0.44 (1.06)	1.00	0.95 (0.15)	0.0002

ρe, environmental correlation coefficient; ρg, genetic correlation coefficient; NC, not computable; SE, standard error.

Discussion

The schizophrenia phenome database is designed to complement large bodies of genetic data. The objective of the database is to accelerate the discovery of genes that contribute to schizophrenia, a common and often disabling disease. One key to making data valuable to the community is to provide public access. Value could be added to the schizophrenia phenome database by incorporating data from additional studies. It is also worth considering the combination of these clinical data with physiological data from brain imaging, hypothalamic–pituitary–adrenal axis, evoked potential, and neuropsychological studies. Further steps that could be added to the existing dataset include data reduction through techniques such as factor analysis. These factors could then be tested for familiality, and the factor scores could be used as phenotypes for genetic study.

According to the present results, aberrations in several psychopathologic dimensions could form the complexity of schizophrenic syndrome because of genetic–environment coactions or interactions. Five heritable dimensions (high obsessive–compulsive, high interpersonal–sensitivity, high depression, high hostility, and high phobia) could qualitatively differentiate the schizophrenia patient group from the first-degree relatives and control group. Genetic and environmental correlations with schizophrenia phenotype for psychopathologic dimensions were suggested.

This study replicates previous results that some psychopathologic dimensions including personality are heritable and familial in families with schizophrenia and can be very promising endophenotypic markers for schizophrenia, although there are several limitations including the recruited family and phenotyping.^41,42 It is very critical, but very difficult to recruit sufficient numbers of well-matched cases and controls with respect to age and sex for pedigree–control comparson analysis. Given that the present schizophrenia and control subjects were poorly matched, we also analyzed the data after adjusting for age (Table 3). We are now in the process of recruiting a larger cohort of matched control samples to further confirm the present findings.

The SCL questionnaire is the representative tool for suggesting that symptomatic dimensions are continuous with psychopathologic dimensions in schizophrenia. The validity of the anxiety subscale of the SCL-90-R was confirmed for examining the longitudinal relationship between personal and social performance (PSP) and the anxiety symptoms in schizophrenia. Two psychosis syndromes derived from the SCL-90-R – schizotypal signs and schizophrenia nuclear symptoms – were analyzed in this study to examine the impact of childhood adversity on the onset and course of subclinical psychosis symptoms. In addition, two measures of subclinical psychosis derived from the SCL-90-R, namely schizotypal signs (STS) and schizophrenia nuclear symptoms (SNS), were applied for deconstructing subclinical psychosis into latent-state and trait variables over a 30-year time span. In the investigation of a connection between neurological soft signs (NSS) and psychometrically identified schizotypy in a sample of young conscripts, subjects completed the schizotypal personality questionnaire (SPQ), the SCL-90-R, and Raven’s progressive matrices (RPM).⁴³ Subclinical psychosis symptoms in young adults were risk factors for subsequent common mental disorders in the data analysis from the prospective Zurich cohort study using two psychosis subscales – ‘schizotypal signs’ and ‘schizophrenia nuclear symptoms’ – derived from the SCL-90-R that measured subclinical psychosis symptoms in 1979.⁴⁴ The psychosis symptom dimensions were derived from the SCL-90-R, and were regressed on a broad range of known risk factors for psychosis. Risk factors typically assigned to schizophrenia and other psychotic disorders – cannabis use, childhood adversity, reading and writing difficulties, attention deficit hyperactivity disorder (ADHD), psychiatric disorders, and addiction in parents and the extended family – are also relevant at subclinical levels. Associations of sociodemographic characteristics with non-clinical psychotic symptoms and other psychiatric symptoms using the SCL-90 were suggested.⁴⁵ The SCL-90-R appears to be a valuable tool to distinguish patients with schizophrenia from outpatients with various medical conditions including rheumatoid arthritis, suggesting the negative association at a dimensional level. In total, 938 Swiss conscripts were assessed with the self-screen-prodrome (SPro), the Eppendorf schizophrenia inventory (ESI) and the SCL-90-R to examine aspects of validity of the SPro as a new screening tool for prodromal states of psychosis in a military sample.⁴⁶ A group of scales from items on the SCL-90 was created to identify eight common psychiatric diagnoses. Subjective response was rated with the SCL-90-R for assessing clinical outcomes in a comparative study for maintenance treatment of schizophrenia with risperidone or haloperidol during 2-year follow up.⁴⁷ The usefulness of the Minnesota multiphasic personality inventory (MMPI), the original and revised versions of the Millon clinical multiaxial inventory (MCMI and MCMI-II), and the SCL-90-R was confirmed for the diagnosis and assessment of depression, mania, and psychosis in a heterogeneous group of 272 psychiatric inpatients.⁴⁸ The extent of agreement between schizophrenia patients, hospital clinicians, and independent evaluators’ views of the patients’ symptoms and community functioning status was identified using the SCL-90, the Denver community mental health questionnaire, and the personal adjustment and role skills inventory. The effects of treatment were assessed by the SCL-90 in a double-blind placebo-controlled study for evaluating the effectiveness of high-dose diazepam in schizophrenia.^43–56

The present study could be an important stepping stone on the path to solving the thus-far mysterious equations describing schizophrenia. Most areas in positional genetic variations and environmental factors, however, remain doubtful as loaded variables of equations for causing this syndrome.

Most importantly, future genome-wide linkage and association studies with more complete pedigrees are expected. Then, Family- Based Association Test analyses in families with subtyped schizophrenia probands according to personality, working memory, and cognition, in addition to previously described quantitative traits will facilitate fine mapping analyses for identifying the candidate genes of schizophrenia, a goliath task for psychiatrists.