An association study of PCQAP polymorphisms and schizophrenia.

INTRODUCTION: PCQAP is a member of the mediator family of transcription co-activators that is found in the region of 22q11, which is consistently deleted in DiGeorges/velocranialfacial (VCF) syndrome. As such, it is a gene of interest to behavioral geneticists because VCF is also associated with a high rate of psychosis and because defects in other mediator genes have been linked to psychosis and abnormal neurodevelopmental abnormalities. Recently, DeLuca and colleagues reported that polymorphisms in a trinucleotide repeat in exon 7 of PCQAP were associated with schizophrenia in a case-control study of Italian schizophrenics. OBJECTIVE AND METHODS: To confirm and extend the prior findings, we conducted a case-control association analysis using DNA from 233 schizophrenics and 371 random controls. RESULTS: Unfortunately, we did not find any significant differences in the distribution of CAG repeat alleles between subjects and controls. CONCLUSIONS: These findings limit the role of exon 7 PCQAP polymorphisms in the pathogenesis of schizophrenia.

Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription.

The serotonin transporter (5HTT; chromosomal location 17q12) is an important regulator of serotonergic neurotransmission and is the site of action for a number of antidepressant medications. Sequence variation at a VNTR known as the 5HTTLPR, which is 1.4 kb upstream of the translation start of 5HTT, has been associated in some studies with increased vulnerability to depression, neuroticism, and autism. Support for these clinical observations has included laboratory findings that 5HTTLPR variation is associated with changes in 5HTT gene translation. We re-examined these earlier laboratory findings by directly measuring 5HTT mRNA levels and genotyping four loci spanning the 5HTT gene using RNA and DNA prepared from 85 independent lymphoblast cell lines. Using this data, haplotypes were inferred and the resulting single point and haplotypes data analyzed by univariate and regression analyses. Consistent with the original findings, we found a significant effect of the 5HTTLPR on mRNA production. In contrast to previous reports, the effect on 5HTT mRNA production appeared to be mediated through an additive, not dominant, mechanism. Neither genotype nor haplotype at three other 5HTT loci were associated with alterations in mRNA production, although the small number of samples homozygous for the three most common haplotypes limits these findings. We conclude that further examination of the role of 5HTT sequence variation in regulating 5HTT mRNA production is warranted.

Polymorphism analysis of HOPA: a candidate gene for schizophrenia.

HOPA is a 25 kb Xq13 gene that codes for a member of the thyroid receptor co-activator protein (TRAP) family of nuclear receptor co-activators. In our prior research, polymorphisms in the opposite paired (Opa) domain of HOPA have been associated with a syndrome of aberrant behavior, most prominently psychosis, and hypothyroidism. These Opa domain polymorphisms are intriguing because subsequent research has demonstrated that changes in the Opa domain of the C. elegans orthologue of HOPA results in altered neurogenesis and release of transcriptional suppression. In an effort to determine whether other allelic polymorphisms in this gene exist and may potentially contribute to increased susceptibility to neuropsychiatric illness, we have performed single stranded conformational polymorphism (SSCP) analysis of all 45 exons and each of the two potential promoter regions of HOPA using DNA from a panel of patients with psychosis. We found a rare promoter polymorphism in an individual with schizoaffective disorder and extremely low thyroid stimulating hormone (TSH). The most common exonic polymorphism in HOPA is the previously demonstrated HOPA(12 bp) polymorphism. Transmission disequilibrium analysis of the HOPA(12 bp) polymorphism showed segregation with affected status in six of eight instances. We suggest that this evidence supports previous associations of HOPA(12 bp) with a broad range of neuropsychiatric illness and conclude that further studies of this uncommon polymorphism are merited.

Association of the HOPA12bp allele with a large X-chromosome haplotype and positive symptom schizophrenia.

HOPA is a X-chromosome gene that encodes an essential nuclear receptor co-activator. Previously, we have demonstrated that an exonic polymorphism, termed HOPA(12bp), in the Opa (Opposite Paired) domain of this gene that is critical for neuronal growth and differentiation is associated with a low risk for schizophrenia. But curiously, we have also noted that all HOPA(12bp) probands have the same haplotype immediately surrounding the HOPA(12bp), and other investigators have found evidence of population stratification with the HOPA(12bp) allele. Since deleterious alleles are weeded from the population, and the HOPA(12bp) allele is not rare, these prior findings suggest the possibility that positive selection may be occurring with respect to the HOPA(12bp) allele and that unique phenotypic features may be associated with this allele. To test these hypotheses, we analyzed symptom data collected from schizophrenic probands and conducted haplotyping studies around the HOPA(12bp) polymorphism. Consistent with our hypotheses, genotyping studies of 43 unrelated HOPA(12bp) males and 137 HOPA(wild) males demonstrated that the HOPA(12bp) allele is associated with a large conserved DNA haplotype that extends over several genes known to be critical for human survival. Furthermore, ANOVA analysis of symptom data demonstrated that HOPA(12bp) schizophrenic probands (n = 14) have significantly lower severity of negative symptoms (P < 0.002) and better attention (P < 0.002) than matched controls (n = 30). Taken together, these findings further refine the behavioral endophenotype associated with the HOPA(12bp) allele and suggest that the sequence surrounding HOPA may need to be considered to fully understand the molecular basis of the phenotype associated with the HOPA(12bp) allele.

Associations of the serotonin transporter promoter polymorphism with aggressivity, attention deficit, and conduct disorder in an adoptee population.

Prior studies of the Iowa Adoption cohorts have demonstrated that the degree of adoptee aggressiveness and conduct disorder has a significant genetic component. Other studies have implicated the neurotransmitter serotonin or polymorphisms in the serotonin transporter gene (5HTT) as an important source of variability in "externalizing" behaviors such as aggressivity, conduct disorder, and attention deficit-hyperactivity disorders (ADHD). Following this lead, we genotyped a subgroup of adoptees (n = 87) at high risk for these kinds of disorders with respect to the serotonin-transporter-linked promoter region (5HTTLPR) polymorphism, and used ordinal logistic regression to conduct an association study. Primary analysis failed to detect a main effect between 5HTTLPR status and subscales of aggressivity, conduct disorder, or attention deficit. However, when biologic parent status and sex of proband were considered, certain interactions between 5HTTLPR and other genetic risk factors were evident. One type of interaction with the LL variant of 5HTTLPR increased externalizing behavior in individuals with antisocial biologic parentage; a second interaction with one or more 5HTTLPR short variants (SS or SL) appeared to increase externalizing behaviors in conjunction with a genetic diathesis for alcoholism. Gender of adoptee also appeared to interact with 5HTTLPR. Male individuals with the short variant were more likely to have higher symptom counts for conduct disorder, aggressivity, and ADHD. In contrast, among females, the short variant (SS, SL) was associated with lower levels of such behavior. The results support the hypothesis that gene-biological family history interactions are involved in the externalizing behaviors studied and constitute interesting findings for future replication.

Association of an exonic LDHA polymorphism with altered respiratory response in probands at high risk for panic disorder.

Panic disorder (PD) is a clinical syndrome characterized by recurrent discrete episodes of fear accompanied by a variety of physiological and psychological symptoms, often with prominent respiratory components. A series of clinical observations has led some investigators to hypothesize that subtle alterations in ventilatory regulation are integral to at least a subtype of PD. In order to identify genetic factors that might predispose individuals to these alterations in ventilatory response, we conducted single stranded conformation polymorphism analysis across the exons of the lactate dehydrogenase A and B genes (LDHA and LDHB) using DNA prepared from 86 subjects previously characterized by respiratory response to a CO(2) challenge with a variable genetic loading for PD. Remarkably, a single conserved LDHA exon 5 haplotype conferred increased risk for a paradoxical ventilatory response pattern to CO(2) inhalation which robustly separated well subjects at high risk for PD from low-risk control subjects. But, comparison of LDHA exon 5 genotypes in PD probands (n = 25) to that of random newborn controls (n = 182) did not demonstrate any significant differences. Given the pivotal role of LDH in the metabolism of lactate, a known inducer of panic attacks, and the dependence of LDH activity on cell pH, we suggest that LDHA polymorphisms may contribute to the variability to CO(2) respiratory challenge.

Role of elastin polymorphisms in panic disorder.

Panic disorder (PD) is a complex neuropsychiatric disorder that has been associated with an increased frequency of mitral valve prolapse. Elastin is a prominent component of mitral valves and, in a genome screen of 23 pedigrees with PD, we found evidence of linkage to the region of chromosome 7 that contains the elastin gene (ELN). Therefore, we examined the minimal essential promoter and coding regions of ELN in 23 independent probands from the families in our linkage studies using single strand conformational polymorphism analysis. We found three polymorphisms including one that coded for a non-conservative amino acid change. However, none of these polymorphisms were associated with panic disorder in a case-control analysis or linked to it in multiplex pedigrees. In our pedigrees, exonic polymorphisms in ELN do not play a major role in the genetic vulnerability to PD.

The association of the D2S2944 124 bp allele with recurrent early onset major depressive disorder in women.

Major depressive disorder (MDD) and substance use disorders (SUD) are complex behavioral disorders with 40-50% heritability. Recently, Zubenko and colleagues reported that the 124 bp allele of D2S2944, a tetranucleotide repeat marker on 2q35, is strongly associated with recurrent, early onset MDD (RE-MDD) and alcohol use disorders in women. To test this hypothesis, we examined the association of the 124 bp allele in a subset of 171 adoptees from the Iowa Adoption Studies, a population with high rates of MDD and SUD. We report that in our population, the 124 bp allele significantly associated with RE-MDD in women. There was slight evidence of an increased of SUD in women with the 124 bp allele with the rate of cannabis use disorders reaching statistical significance (P < 0.04) before correction for multiple comparisons. Given the history of prior studies implicating 2q35 as a locus encoding vulnerability to co-morbid alcoholism and depression, these findings strongly suggest that sequence variation conveying increased susceptibility to MDD and possibly SUD is in close proximity to D2S2944.

The association of a HOPA polymorphism with major depression and phobia.

Thyroid hormone has a prominent role in the development and homeostasis of the central nervous system (CNS). Consequently, genes participating in thyroid hormone receptor (THR)-mediated signal transduction are prime candidates for neuropsychiatric illness susceptibility factors. Previously, we have associated exonic polymorphisms in a Xq13 thyroid receptor coactivator named HOPA with a modest increase in vulnerability to a broad spectrum of neuropsychiatric illness, including depression, psychosis, and hypothyroidism. In order to test and extend these findings, we have now examined the relationship between HOPA polymorphisms and neuropsychiatric illness in a cohort of Iowa adoptees. Consistent with our prior findings, HOPA polymorphisms were associated with an increased risk for major depression. There was suggestive evidence that the increased psychiatric morbidity in these subjects could represent epistasis, e.g., an interaction between the HOPA variant and a genetic diathesis for another psychiatric condition such as biologic parent antisocial behavior. Information about biologic parent behavior and the adoptive home environment was used to determine depressive symptoms attributable to gene-environment interaction. HOPA variant subjects continued to show significant differences in depressive symptoms when controlling for gene-environment interaction. Finally, because obesity is associated with hypothyroidism and HOPA polymorphisms are associated with hypothyroidism, we analyzed weight with respect to HOPA allele status. We found that that HOPA polymorphisms were associated with increased risk for obesity (P <.001). In summary, we conclude that HOPA polymorphisms may be a moderate risk factor for increased susceptibility to a broad spectrum of neuropsychiatric illness and hypothesize that the type of illness manifested might be related to a separate genetic diathesis.