Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history.

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Schizophrenia is a genetically and clinically heterogeneous disorder. Genetic risk factors for the disorder may differ between the sexes or between multiply affected families compared to cases with no family history. Additionally, limited data support a genetic basis for variation in onset and severity, but specific loci have not been identified. We performed genome-wide association studies (GWAS) examining genetic influences on age at onset (AAO) and illness severity as well as specific risk by sex or family history status using up to 2762 cases and 3187 controls from the International Schizophrenia Consortium (ISC). Subjects with a family history of schizophrenia demonstrated a slightly lower average AAO that was not significant following multiple testing correction (p=.048), but no differences in illness severity were observed by family history status (p=.51). Consistent with prior reports, we observed earlier AAO (p=.005) and a more severe course of illness for men (p=.002). Family history positive analyses showed the greatest association with KIF5C (p=1.96×10(-8)), however, genetic risk burden overall does not differ by family history. Separate association analyses for males and females revealed no significant sex-specific associations. The top GWAS hit for AAO was near the olfactory receptor gene OR2K2 (p=1.52×10(-7)). Analyses of illness severity (episodic vs. continuous) implicated variation in ST18 (p=8.24×10(-7)). These results confirm recognized demographic relationships but do not support a simplified genetic architecture for schizophrenia subtypes based on these variables.

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Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.

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Schizophrenia is a genetically and clinically heterogeneous disorder. Genetic risk factors for the disorder may differ between the sexes or between multiply affected families compared to cases with no family history. Additionally, limited data support a genetic basis for variation in onset and severity, but specific loci have not been identified. We performed genome-wide association studies (GWAS) examining genetic influences on age at onset (AAO) and illness severity as well as specific risk by sex or family history status using up to 2762 cases and 3187 controls from the International Schizophrenia Consortium (ISC). Subjects with a family history of schizophrenia demonstrated a slightly lower average AAO that was not significant following multiple testing correction (p=.048), but no differences in illness severity were observed by family history status (p=.51). Consistent with prior reports, we observed earlier AAO (p=.005) and a more severe course of illness for men (p=.002). Family history positive analyses showed the greatest association with KIF5C (p=1.96×10(-8)), however, genetic risk burden overall does not differ by family history. Separate association analyses for males and females revealed no significant sex-specific associations. The top GWAS hit for AAO was near the olfactory receptor gene OR2K2 (p=1.52×10(-7)). Analyses of illness severity (episodic vs. continuous) implicated variation in ST18 (p=8.24×10(-7)). These results confirm recognized demographic relationships but do not support a simplified genetic architecture for schizophrenia subtypes based on these variables.

2014Nov
JAMA Neurol
JAMA Neurol 2014 Nov;71(11):1394-404
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Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium.
The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.
Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242).
We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.

A large number of studies has investigated the hypothesis that DRD4 48 bp variable number of tandem repeat (VNTR) polymorphism is involved in the etiology of schizophrenia and bipolar disorder. However, the results are inconsistent likely due to genetic and phenotypic heterogeneity. Age at onset (AAO) is considered an important alternate phenotype for genetic investigations of psychiatric disorders. In the present study, the DRD4 VNTR 7 repeat allele (7R) was examined in 477 patients with major psychoses. Age at onset was defined as the age of first psychotic episode for schizophrenia and the age at appearance of first clinically recognized symptoms for the bipolar sample. Our results showed an interaction between sex and DRD4 genotypes among schizophrenia patients (n=203, β=.213, p=.017). On comparing AAO between carriers and non-carriers of the 7R, we observed that females with 7R present had later onset (p=.021). The effect was not observed for males. In the sample with bipolar disorder, we observed significant association between DRD4 7R-genotype and AAO (n=274, β=-.148, p=.012). No interaction was observed between sex and genotypic groups of the bipolar sample. The 7R was associated with early onset of the bipolar illness (p=.028). In summary, our results suggest that the 7R is associated with AAO in both schizophrenia and bipolar disorders. The effect was observed across both sexes in bipolar disorder, but specifically in females for schizophrenia.

The etiology of schizophrenia is believed to include genetic and nongenetic factors, with the pathogenesis involving abnormal neurodevelopment. We investigated whether mild head injury during brain maturation plays a role in the expression of schizophrenia in multiply affected families.
We compared the history and severity of head injuries in childhood (age, < or =10 years) and through adolescence (age, < or =17 years) in 67 subjects with narrowly defined schizophrenia and 102 of their unaffected siblings from 23 multiply affected families. In subjects with schizophrenia, only head injuries preceding the onset of psychosis were considered.
Subjects in the schizophrenia group (n = 16 [23.9%]) were more likely than the unaffected siblings group (n = 12 [11.8%]) to have a history of childhood head injury (P =.04; odds ratio, 2.35 [95% confidence interval, 1.03-5.36]). Subjects in the schizophrenia group with a history of childhood head injury had a significantly younger median age at onset of psychosis (20 years) compared with those with no such history (25 years; z = -2.98; P =.003). The severity of head injury ranged from minimal to mild, including concussions, but within this narrow range, severity was correlated with younger age at onset (r(s) = -0.66; P =.005). Head injury occurred a median of 12 years before the onset of psychosis. Results were similar if head injuries during adolescence were included, but did not achieve statistical significance.
Mild childhood head injury may play a role in the expression of schizophrenia in families with a strong genetic predisposition. Prospective studies of mild head injury should consider genetic predisposition for possible long-term neurobehavioral sequelae.

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Affiliation Details

  • Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
  • Neuropsychiatric Genetics Research Group
Affiliation Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.