Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Background

Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-d-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine.

Methods

We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED.

Results

We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA.

Limitations

Given the limited sample size, the results are tentative until replication.

Conclusion

Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.     

Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population

Objective

CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder.

Methods

We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G).

Results

There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive.

Conclusion

We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required.     

Neuregulin 1 genetic variation and anterior cingulum integrity in patients with schizophrenia and healthy controls

Background

Neuregulin1 (NRG1) influences the development of white matter connectivity and is implicated in genetic susceptibility to schizophrenia. The cingulum bundle is a white matter structure implicated in schizophrenia. Its anterior component is especially implicated, as it provides reciprocal connections between brain regions with prominent involvement in the disorder. Abnormalities in the structural integrity of the anterior cingulum in patients with schizophrenia have been reported previously. The present study investigated the potential contribution of NRG1 variation to anterior cingulum abnormalities in participants with schizophrenia.

Methods

We studied 31 men with schizophrenia and 36 healthy men using diffusion tensor imaging to investigate the association between fractional anisotropy in the anterior cingulum and a single-nucleotide polymorphism (SNP8NRG221533: rs35753505) of NRG1.

Results

Consistent with previous reports, fractional anisotropy was significantly reduced in the anterior cingulum in the schizophrenia group. Moreover, the results revealed a significant group (schizophrenia, control) by genotype (C/C, T carriers, including CT and TT) interaction between genetic variation in NRG1 and diagnosis of schizophrenia, such that the patients with the T allele for SNP8NRG221533 had significantly decreased anterior cingulum fractional anisotropy compared with patients homozygous for the C allele and healthy controls who were T carriers.

Limitations

Limitations of our study included the small sample size of the TT subgroup and our use of only fractional anisotropy as an index of myelin integrity. In addition, the use of diffusion tensor imaging acquisition methods limited our ability to study other brain regions that may be involved in schizophrenia.

Conclusion

Our results suggest that NRG1 variation may play a role in the pathophysiology of anterior cingulum abnormalities in patients with schizophrenia.     

Obstetric Complications as Risk Factors for Schizophrenia Spectrum Psychoses in Offspring of Mothers With Psychotic Disorder

Background:

Obstetric complications have predicted future development of schizophrenia in previous studies, but they are also more common in mothers with schizophrenia. The aims of this study were to compare the occurrence of obstetric complications in children of mothers with schizophrenia spectrum psychoses and control children, and to investigate whether obstetric complications predicted children’s psychiatric morbidity.

Method:

The Helsinki High-Risk (HR) Study monitors females born between 1916 and 1948 and treated for schizophrenia spectrum disorders in Helsinki psychiatric hospitals, their offspring born between 1941 and 1977, and controls. We examined information on obstetric complications and neonatal health of 271 HR and 242 control offspring. We compared the frequency of obstetric complications and neonatal health problems in the HR group vs controls and in HR children who later developed psychotic disorders vs healthy HR children. A Cox regression model was used to assess whether problems in pregnancy or delivery predicted psychiatric morbidity within the HR group.

Results:

Few differences between HR and control offspring were found in obstetric complications. Within the HR group, infections (hazard rate ratio [HRR] 3.73, 95% CI 1.27–11.01), hypertension during pregnancy (HRR 4.10, 95% CI 1.15–14.58), and placental abnormalities (HRR 4.09, 95% CI 1.59–10.49) were associated with elevated risk of schizophrenia spectrum psychoses.

Conclusions:

Common medical problems during pregnancy were associated with increased risk of schizophrenia spectrum psychoses in offspring of mothers with schizophrenia spectrum psychoses. These results underline the role of the prenatal period in the development of schizophrenia and the importance of careful monitoring of pregnancies of mothers with psychotic disorder.Key words: schizophrenia, High-Risk Study, obstetric complications, risk factors, prenatal infections     

A Disrupted-in-Schizophrenia 1 Gene Variant is Associated with Clinical Symptomatology in Patients with First-Episode Psychosis

Objective

DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis.

Methods

Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects.

Results

Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers.

Conclusion

DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.     

Association Study of Fibroblast Growth Factor 2 and Fibroblast Growth Factor Receptors Gene Polymorphism in Korean Ossification of the Posterior Longitudinal Ligament Patients

Objective

The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of fibroblast growth factor (FGF) 2 gene and fibroblast growth factor receptor (FGFR) genes are associated with ossification of the posterior longitudinal ligament (OPLL).

Methods

A total of 157 patients with OPLL and 222 controls were recruited for a case control association study investigating the relationship between SNPs of FGF2, FGFR1, FGFR2 and OPLL. To identify the association among polymorphisms of FGF2 gene, FGFR1, FGFR2 genes and OPLL, the authors genotyped 9 SNPs of the genes (FGF2 : rs1476217, rs308395, rs308397, and rs3747676; FGFR1 : rs13317 and rs2467531; FGFR2 : rs755793, rs1047100, and rs3135831) using direct sequencing method. SNPs data were analyzed using the SNPStats, SNPAnalyzer, Haploview, and Helixtree programs.

Results

Of the SNPs, a SNP (rs13317) in FGFR1 was significantly associated with the susceptibility of OPLL in the codominant (odds ratio=1.35, 95% confidence interval=1.01-1.81, p=0.048) and recessive model (odds ratio=2.00, 95% confidence interval=1.11-3.59, p=0.020). The analysis adjusted for associated condition showed that the SNP of rs1476217 (p=0.03), rs3747676 (p=0.01) polymorphisms in the FGF2 were associated with diffuse idiopathic skeletal hyperostosis (DISH) and rs1476217 (p=0.01) in the FGF2 was associated with ossification of the ligament flavum (OLF).

Conclusion

The results of the present study revealed that an FGFR1 SNP was significantly associated with OPLL and that a SNP in FGF2 was associated with conditions that were comorbid with OPLL (DISH and OLF).     

Association of schizophrenia with the rs821633 polymorphism in the DISC1 gene among Han Chinese

Background

Previous studies report that various single nucleotide polymorphisms (SNP) in the Disrupted-in Schizophrenia 1 (DISC1) gene are closely associated with schizophrenia, but there are no studies that assess the relationship of age of onset of schizophrenia with these SNPs.

Objective

Investigate the relationship between the rs821633 SNP in the DISC1 gene and the occurrence and age of onset of schizophrenia in Han Chinese.

Methods

We used the TaqMan genotyping technology to examine the rs821633 SNP in the DISC1 gene among 315 individuals who developed schizophrenia prior to 19 years of age (‘early-onset’), 407 individuals who developed schizophrenia when 19 years of age or older (‘late-onset’), and 482 healthy controls. We used survival analyses to investigate the relationship between the rs821633(C) risk allele and the age of onset of schizophrenia.

Results

Compared to the prevalence in healthy controls, the prevalence of the C/C genotype of rs821633 and of the C allele in rs821633 were significantly greater in individuals with early-onset schizophrenia (X²=7.17, df=1, p=0.007; X²=7.20, df=2, p=0.032) and significantly greater in individuals with late-onset schizophrenia (X²=5.36, df=1, p=0.022; X²=6.58, df=2, p=0.041). However, there were no significant differences in the prevalence of the C/C genotype or the C allele between individuals with early-onset and late-onset schizophrenia. Kaplan-Meier survival analyses found no significant association between the rs821633(C) risk allele and age of onset in schizophrenia.

Conclusion

We confirm the association of polymorphism in the rs821633 SNP in the DISC1 gene with schizophrenia among Han Chinese, but we found no association between the rs821633(C) risk allele and the age of onset in individuals with schizophrenia.     

Disrupted-in-Schizophrenia-1 SNPs and Susceptibility to Schizophrenia: Evidence from Malaysia

Objective

Even though the role of the DICS1 gene as a risk factor for schizophrenia is still unclear, there is substantial evidence from functional and cell biology studies that supports the connection of the gene with schizophrenia. The studies associating the DISC1 gene with schizophrenia in Asian populations are limited to East-Asian populations. Our study examined several DISC1 markers of schizophrenia that were identified in the Caucasian and East-Asian populations in Malaysia and assessed the role of rs2509382, which is located at 11q14.3, the mutual translocation region of the famous DISC1 translocation [t (1; 11) (p42.1; q14.3)].

Methods

We genotyped eleven single-neucleotide polymorphism (SNPs) within or related to DISC1 (rs821597, rs821616, rs4658971, rs1538979, rs843979, rs2812385, rs1407599, rs4658890, and rs2509382) using the PCR-RFLP methods.

Results

In all, there were 575 participants (225 schizophrenic patients and 350 healthy controls) of either Malay or Chinese ethnicity. The case-control analyses found two SNPs that were associated with schizophrenia [rs4658971 (p=0.030; OR=1.43 (1.35-1.99) and rs1538979-(p=0.036; OR=1.35 (1.02-1.80)] and rs2509382-susceptibility among the males schizophrenics [p=0.0082; OR=2.16 (1.22-3.81)]. This is similar to the meta-analysis findings for the Caucasian populations.

Conclusion

The study supports the notion that the DISC1 gene is a marker of schizophrenia susceptibility and that rs2509382 in the mutual DISC1 translocation region is a susceptibility marker for schizophrenia among males in Malaysia. However, the finding of the study is limited due to possible genetic stratification and the small sample size.     

Facial Emotion Recognition in Schizophrenia: The Impact of Gender

Objective

Previous studies reported gender differences for facial emotion recognition in healthy people, with women performing better than men. Few studies that examined gender differences for facial emotion recognition in schizophrenia brought out inconsistent findings. The aim of this study is to investigate gender differences for facial emotion identification and discrimination abilities in patients with schizophrenia.

Methods

35 female and 35 male patients with schizophrenia, along with 35 female and 35 male healthy controls were included in the study. All the subjects were evaluated with Facial Emotion Identification Test (FEIT), Facial Emotion Discrimination Test (FEDT), and Benton Facial Recognition Test (BFRT). Patients'' psychopathological symptoms were rated by means of the Positive and Negative Syndrome Scale (PANSS).

Results

Male patients performed significantly worse than female patients on FEIT total, and negative scores. Male controls performed significantly worse than female controls on FEIT total and negative scores. On all tasks, female patients performed comparable with controls. Male patients performed significantly worse than controls on FEIT, and FEDT.

Conclusion

Women with schizophrenia outperformed men for facial emotion recognition ability in a pattern that is similar with the healthy controls. It could be claimed that male patients with schizophrenia need special consideration for emotion perception deficits.     

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder

Background

Previous studies have suggested that there may be a parent-of-origin effect for attention-deficit/hyperactivity disorder (ADHD) candidate genes. The objective of the present study was to investigate parent-of-origin effects using a genome-wide association analysis of the International Multicentre ADHD Genetics (IMAGE) study sample.

Methods

Family-based association analysis for ADHD using 846 ADHD probands and their parents was performed using the PLINK program, and parent-of-origin effects were studied using a Z score for the difference in paternal versus maternal odds ratios.

Results

We identified 44 single nucleotide polymorphisms (SNPs) showing parent-of-origin effects at a significance level of p < 0.001. The most significant SNP, rs7614907, is at position 3q13.33 in the CDGAP gene (p = 0.000064 for parent-of-origin effect). Furthermore, 2 genes (FAS and PDLIM1) showed moderate parent-of-origin effects (p = 0.00086 for rs9658691 and p = 0.00077 for rs11188249) and strong maternal transmission (p = 0.000059 for rs9658691 and p = 0.0000068 for rs11188249). In addition, ZNF775 showed a moderate parent-of-origin effect (p = 0.00036 for rs7790549) and strong paternal transmission (p = 0.000041 for rs7790549).

Limitations

We only had 1 sample available for analysis.

Conclusion

These results suggest several genes or regions with moderate parent-of-origin effects, and these findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in ADHD.     

The Effect of Paternal Age on Relapse in First-Episode Schizophrenia

Objective:

Multiple etiological and prognostic factors have been implied in schizophrenia and its outcome. Advanced paternal age has been reported as a risk factor in schizophrenia. Whether this may affect schizophrenia outcome was not previously studied. We hypothesized that advanced paternal age may have a negative effect on the outcome of relapse in schizophrenia.

Method:

We interviewed 191 patients with first-episode schizophrenia and their relatives for parental ages, sociodemographic factors at birth, birth rank, family history of psychotic disorders, and obstetric complications. The outcome measure was the presence of relapse at the end of the first year of treatment.

Results:

In the 1-year follow-up period, 42 (22%) patients experienced 1 or more relapses. The mean paternal age was 34.62 years (SD 7.69). Patients who relapsed had significantly higher paternal age, poorer medication adherence, were female, and were hospitalized at onset, compared with patients who did not relapse. A multivariate regression analysis showed that advanced paternal age (OR 1.05, 95% CI 1.01 to 1.10), medication nonadherence (OR 2.37, 95% CI 1.12 to 4.99), and female sex (OR 2.44, 95% CI 1.14 to 5.24) independently contributed to a higher risk of relapse. Analysis between different paternal age groups found a significantly higher relapse rate with paternal age over 40.

Conclusions:

Advanced paternal age is found to be modestly but significantly related to more relapses, and such an effect is the strongest at a cut-off of paternal age of 40 years or older. The effect is less likely to be mediated through less effective parental supervision or nonadherence to medication. Other possible biological mechanisms need further explorations.     

An exploratory model for G × E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes

Background

Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls.

Methods

Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records.

Results

Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume.

Conclusions

The findings suggest a gene–environment (G × E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples.     

Positive association of the pericentrin (PCNT) gene with major depressive disorder in the Japanese population

Background

Pericentrin (PCNT) interacts with disruption-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). We sought to determine whether the PCNT gene is implicated in MDD.

Methods

We performed case–control association analyses in the Japanese population. We analyzed 9 single nucleotide polymorphisms (SNPs) in 173 patients with MDD and 348 healthy controls.

Results

We found a significant allelic association between 3 SNPs (rs3788265, rs2073376 and rs2073380) of the PCNT gene and MDD (p = 0.006, 0.005 and 0.021, respectively). After correction for multiple testing, 2 SNPs (rs3788265 and rs2073376) retained significant allelic associations with MDD. In addition, we found a significant association between the 2 marker haplotypes (r3788265 and rs2073376) and MDD (permutation p = 0.011).

Limitations

Our sample was small and comprised only Japanese participants. In addition, owing to the late onset of MDD, it is possible that the disorder will develop in at least some participants in our control group. Finally, we did not show how SNPs of the PCNT gene alter its function.

Conclusion

Our results suggest that genetic variations in the PCNT gene may play a significant role in the etiology of MDD in the Japanese population.     

Effect of the Dysbindin Gene on Antimanic Agents in Patients with Bipolar I Disorder

Objective

We previously reported an association between dysbindin gene (DTNBP1) variants and bipolar I disorder (BID). This paper expands upon previous findings suggesting that DTNBP1 variants may play a role in the response to acute mood stabilizer treatment.

Methods

A total of 45 BID patients were treated with antimanic agents (lithium, valproate, or carbamazepine) for an average of 36.52 (±19.87) days. After treatment, the patients were evaluated using the Clinical Global Impression (CGI) scale and the Young Mania Rating Scale (YMRS) and genotyped for their DTNBP1 variants (rs3213207 A/G, rs1011313 C/T, rs2005976 G/A, rs760761 C/T and rs2619522 A/C).

Results

There was no association between the variants investigated and response to mood stabilizer treatment, even after considering possible stratification factors.

Conclusion

Although the small number of subjects is an important limitation in our study, DTNBP1 does not seem to be involved in acute antimanic efficacy.     

Genotyping Sleep Disorders Patients

Objective

The genetic susceptibility factors underlying sleep disorders might help us predict prognoses and responses to treatment. Several candidate polymorphisms for sleep disorders have been proposed, but there has as yet inadequate replication or validation that the candidates may be useful in the clinical setting.

Methods

To assess the validity of several candidate associations, we obtained saliva deoxyribonucleic acid (DNA) samples and clinical information from 360 consenting research participants who were undergoing clinical polysomnograms. Ten single nucleotide polymorphisms (SNPs) were genotyped. These were thought to be related to depression, circadian sleep disorders, sleep apnea, restless legs syndrome (RLS), excessive sleepiness, or to slow waves in sleep.

Results

With multivariate generalized linear models, the association of TEF rs738499 with depressive symptoms was confirmed. Equivocal statistical evidence of association of rs1801260 (the C3111T SNP in the CLOCK gene) with morningness/eveningness and an association of Apolipoprotein E (APOE) rs429358 with the Epworth Sleepiness Scale (ESS) were obtained, but these associations were not strong enough to be of clinical value by themselves. Predicted association of SNPs with sleep apnea, RLS, and slow wave sleep were not confirmed.

Conclusion

The SNPs tested would not, by themselves, be of use for clinical genotyping in a sleep clinic.     

Association of Toll-Like Receptor 5 Gene Polymorphism with Susceptibility to Ossification of the Posterior Longitudinal Ligament of the Spine in Korean Population

Objective

Ossification of the posterior longitudinal ligament (OPLL) has a strong genetic component. Specific gene polymorphisms may be associated with OPLL in several genes which regulate calcification in chondrocytes, change of extracellular collagen matrix and secretions of many growth factors and cytokines controlling bone morphogenesis. Toll-like receptor 5 (TLR5) may play a role in the pathogenesis of OPLL by intermediate nuclear factor-kappa B (NF-κB). The current study focused on coding single nucleotide polymorphisms (SNPs) of TLR5 for a case-control study investigating the relationship between TLR5 and OPLL in a Korean population.

Methods

A total of 166 patients with OPLL and 231 controls were recruited for a case-control association study investigating the relationship between SNPs of TLR5 gene and OPLL. Four SNPs were genotyped by direct sequencing (rs5744168, rs5744169, rs2072493, and rs5744174). SNP data were analyzed using the SNPStats, SNPAnalyzer, Haploview, and Helixtree programs. Multiple logistic regression analysis with adjustment for age and gender was performed to calculate an odds ratio (OR).

Results

None of SNPs were associated with OPLL in three alternative models (codominant, dominant, and recessive models; p > 0.05). A strong linkage disequilibrium block, including all 4 SNPs, was constructed using the Gabriel method. No haplotype was significantly associated with OPLL in three alternative models.

Conclusion

These results suggest that Toll-like receptor 5 gene may not be associated with ossification of the posterior longitudinal ligament risk in Korean population.     

Evidence for Association between the Brain-Derived Neurotrophic Factor Gene and Panic Disorder: A Novel Haplotype Analysis

Objective

Panic disorder (PD) is a common psychiatric disorder with a complex etiology, and several studies have suggested that it has a genetic component. Brain-derived neurotrophic factor (BDNF) is the most abundant of the neurotrophins in the brain and is recognized for its important role in the survival, differentiation and growth of neurons. Several lines of research have suggested possible associations between the BDNF gene and PD. In this study, we investigated the BDNF 196G/A (rs6265), 11757G/C (rs16917204), and 270C/T (rs56164415) single nucleotide polymorphisms (SNPs) in order to determine an association with PD. We also identified the genetic sequence associations with PD via haplotype analysis.

Methods

Participants in this study included 136 PD patients and 263 healthy controls. Male and female subjects were analyzed separately. The genotype and allele frequencies of the PD patients and controls were analyzed using χ² statistics. Frequencies and haplotype reconstructions were calculated using the SNP analyzer 2.0.

Results

We found no significant statistical differences in the genotype distributions or allele frequencies of the three tested polymorphisms between the PD and control groups. In addition, no differences were found between PD patients and the controls in either male or female subgroups. However, we found that, the frequency of the G-C haplotype for 196G/A and 11757G/C was significantly higher in PD patients than in the controls.

Conclusion

Our result suggest that patients with the G-C haplotype for 196G/A and 11757G/C may be more susceptible to the development of PD. Further studies are needed to replicate the associations that we observed.     

Genome-wide association scan of korean autism spectrum disorders with language delay: a preliminary study

Objective

Communication problems are a prevalent symptom of autism spectrum disorders (ASDs), which have a genetic background. Although several genome-wide studies on ASD have suggested a number of candidate genes, few studies have reported the association or linkage of specific endophenotypes to ASDs.

Methods

Forty-two Korean ASD patients who showed a language delay were enrolled in this study with their parents. We performed a genome-wide scan by using the Affymetrix SNP Array 5.0 platform to identify candidate genes responsible for language delay in ASDs.

Results

We detected candidate single-nucleotide polymorphisms (SNPs) in chromosome 11, rs11212733 (p-value=9.76×10^-6) and rs7125479 (p-value=1.48×10^-4), as a marker of language delay in ASD using the transmission disequilibrium test and multifactor dimensionality reduction test.

Conclusion

Although our results suggest that several SNPs are associated with language delay in ASD, rs11212733 we were not able to observe any significant results after correction of multiple comparisons. This may imply that more samples may be required to identify genes associated with language delay in ASD.     

Polymorphisms of BDNF Gene and Autism Spectrum Disorders: Family Based Association Study with Korean Trios

Objective

Autism spectrum disorders (ASDs) are a group of early childhood-onset neurodevelopmental disorders characterized by deficits in social interaction and language skills, and repetitive behaviors. Brain-derived neurotrophic factor (BDNF) plays a critical role in the differentiation of normal neuronal cells during embryonic and postnatal neuronal development through its neurotrophic effects.

Methods

In this study, we performed a family-based association test (FBAT) between single nucleotide polymorphisms (SNPs; rs6265, rs11030101, rs7103411, and rs7103873) or haplotypes in the BDNF gene and affection status or several quantitative traits characterized by ADI-R with151 Korean trios, including a child diagnosed as ASDs.

Results

While no significant association was found between SNPs or haplotypes and the ASDs disease status, a quantitative transmission disequilibrium test (QTDT) by using quantitative traits identified associations of the SNPs (rs6265 and rs11030101) with a domain score for "Restricted, Repetitive and Stereotyped patterns of behavior" (C domain), especially at the subdomain scores for "encompassing preoccupation or circumscribed pattern of interest" (C1) (rs6265A allele, dominant model, p-value=0.019; rs11030101 A allele, additive model, p-value=0.015) and "preoccupations with part of objects or non-functional elements of material" (C4) (rs11030101 A allele, additive model, p-value=0.015) within the ADI-R diagnostic algorithm. In addition, significant associations were also identified between the haplotypes and these quantitative traits (C1, p-value=0.016; C4, p-value=0.012).

Conclusion

We conclude that BDNF gene polymorphisms have a possible role in the pathogenesis of ASDs.     

Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis

Background

The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation.

Methods

We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter.

Results

In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d′ = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F_6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate–corrected. Risk-allele carriers did not show any regions of reduced white matter volume.

Limitations

The sample size is modest given that a low-frequency variant was being examined.

Conclusion

The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP.