Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: A preliminary study

Obsessive-compulsive disorder (OCD) has been associated with regional volumetric brain abnormalities, which provide promising intermediate phenotypes of the disorder. In this study, volumes of brain regions selected for a priori evidence of association with OCD (orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), thalamus, caudate, putamen, globus pallidus and pituitary) were measured using structural magnetic resonance imaging (MRI) in 20 psychotropic-naïve pediatric OCD patients. We examined the association between these regional brain volumes and a total of 519 single nucleotide polymorphisms (SNPs) from nine glutamatergic candidate genes (DLGAP1, DLGAP2, DLGAP3, GRIN2B, SLC1A1, GRIK2, GRIK3, SLITRK1 and SLITRK5). These genes were selected based on either previous reported association with OCD in humans or evidence from animal models of OCD. After correcting for multiple comparisons by permutation testing, no SNP remained significantly associated with volumetric changes. The strongest trend toward association was identified between two SNPs in DLGAP2 (rs6558484 and rs7014992) and OFC white matter volume. Our other top ranked association findings were with ACC, OFC and thalamus. These preliminary results suggest that sequence variants in glutamate candidate genes may be associated with structural neuroimaging phenotypes of OCD.     

Association between the ionotropic glutamate receptor kainate3 (GRIK3) Ser310Ala polymorphism and schizophrenia in the Indian population

Various studies have been done to check the status of glutamate receptor gene in the pathogenesis of schizophrenia. The T928G (Ser310Ala) polymorphism of ionotropic glutamate receptor kainate 3 gene (GRIK3) and its positive association with schizophrenia was reported in Caucasians, whereas no association of this polymorphism with schizophrenia was shown in two other populations, Chinese and Japanese. However, no literature is available regarding the prevalence of this polymorphism and its association with schizophrenia in the Indian population. As genetic susceptibility profiles in India are often different from those of white Caucasians or Orientals, we investigated the status of Ser310Ala polymorphism of GRIK3 in 100 schizophrenic patients and 100 healthy controls in the Indian population by the PCR-RFLP (restriction fragment length polymorphism) method. A statistically significant difference in the genotype and allelic distributions (P<0.000001 and P=0.01, respectively) of Ser310Ala polymorphism was found in schizophrenics than in control, considering Ala-allele as being associated with the disease (OR=1.7, 95% CI=1.137–2.540). Our study suggests a potential role for GRIK3 for susceptibility to schizophrenia in Indian population.     

Sortilin‐related VPS10 domain containing receptor 1 and Alzheimer's disease‐associated allelic variations preferentially exist in female or type 2 diabetes mellitus patients in southern Han Chinese

Background: Both in vitro and in vivo, overexpression of the sortilin‐related VPS10 domain containing receptor 1 (SORCS1) protein lowers amyloid‐β generation. Recent studies have shown that SORCS1 variations in intron 1 are associated with sporadic Alzheimer's disease (SAD), but the results remain inconsistent. Methods: In order to clarify the role of the SORCS1 gene in southern Han Chinese, we genotyped eight single nucleotide polymorphisms (SNP) of SORCS1 in 128 SAD patients and 92 healthy controls. Results: By dividing patients and controls according to apolipoprotein status, sex and whether they had type 2 diabetes mellitus, we found that rs7907690 C allele frequencies were significantly higher in the Alzheimer's disease (AD) patients with type 2 diabetes mellitus than in the controls (P= 0.041). Also, the rs600879 GG genotype and G allele worked as protective factors of SAD in women (GG genotype, P= 0.007; G allele, P= 0.009). In multilocus analysis, the frequency of an eight‐single nucleotide polymorphism rs601883/rs7907690/rs600879/rs17277986/rs2900717/rs10884399/rs11193170/rs4918280 CCGGACGG haplotype was significantly higher in AD patients (6.3%), especially in female AD patients (9.5%), than in the controls (0.5%) (P= 0.003; P= 0.0002). However, the CTGGACGG haplotype was significantly lower in AD patients (9.3%) than in controls (20.3%) (P= 0.001). The association remained significant even after Bonferroni correction for the number of haplotypes. Conclusion: This study provides evidence that variations in the SORCS1 gene influence susceptibility to SAD in southern Han Chinese. The genetic link between AD and SORCS1 gene variations are influenced by ethnic background, sex and whether an individual has type 2 diabetes mellitus.     

Association between genetic variants of serotonergic and glutamatergic pathways and the concentration of neurometabolites of the anterior cingulate cortex in paediatric patients with obsessive–compulsive disorder

Objectives: The present study aimed to assess the relationship between variability in genes related to the pathophysiology of obsessive–compulsive disorder (OCD) and the concentration of different neurometabolites in the anterior cingulate cortex (ACC). Methods: We concomitantly assessed neurometabolite concentrations using 3-T ¹H-MRS and 262 single nucleotide polymorphism (SNPs) in 35 genes in 41 paediatric OCD patients. Results: There were significant associations, after Bonferroni correction, between the concentration of inositol, glutamate and glutamine, and total choline and five polymorphisms located in genes related to serotonin and glutamate (i.e., the vesicular monoamine transporter 1 gene, SLC18A1 [rs6586896]; the serotonin receptor 1B gene, HTR1B [rs6296 and rs6298]; and the glutamate receptor, ionotropic, AMPA1 gene, GRIA1 [rs707176 and rs2963944]). Conclusions: The association observed between these polymorphisms and the neurometabolite concentrations could indicate the presence of a biological interaction between the serotonin and the glutamate pathways that could be involved in the pathophysiology of OCD. More studies with this methodology could increase our understanding of the aetiology and pathophysiology of OCD in children.     

Reduced functional connectivity within the limbic cortico‐striato‐thalamo‐cortical loop in unmedicated adults with obsessive‐compulsive disorder

Cortico‐striato‐thalamo‐cortical (CSTC) loops project from the cortex to the striatum, then from the striatum to the thalamus via the globus pallidus, and finally from the thalamus back to the cortex again. These loops have been implicated in Obsessive‐Compulsive Disorder (OCD) with particular focus on the limbic CSTC loop, which encompasses the orbitofrontal and anterior cingulate cortices, as well as the ventral striatum. Resting state functional‐connectivity MRI (rs‐fcMRI) studies, which examine temporal correlations in neural activity across brain regions at rest, have examined CSTC loop connectivity in patients with OCD and suggest hyperconnectivity within these loops in medicated adults with OCD. We used rs‐fcMRI to examine functional connectivity within CSTC loops in unmedicated adults with OCD (n = 23) versus healthy controls (HCs) (n = 20). Contrary to prior rs‐fcMRI studies in OCD patients on medications that report hyperconnectivity in the limbic CSTC loop, we found that compared with HCs, unmedicated OCD participants had reduced connectivity within the limbic CSTC loop. Exploratory analyses revealed that reduced connectivity within the limbic CSTC loop correlated with OCD symptom severity in the OCD group. Our finding of limbic loop hypoconnectivity in unmedicted OCD patients highlights the potential confounding effects of antidepressants on connectivity measures and the value of future examinations of the effects of pharmacological and/or behavioral treatments on limbic CSTC loop connectivity. Hum Brain Mapp 35:2852–2860, 2014. © 2013 Wiley Periodicals, Inc .     

A possible association between schizophrenia and GRIK3 polymorphisms in a multicenter sample of Scandinavian origin (SCOPE)

There is considerable evidence of altered glutamatergic signalling in schizophrenia and a polymorphic variant of the GRIK3 glutamate receptor gene on 1p34-33 has previously been associated to this psychotic disorder. We therefore conducted a systematic association study with 30 HapMap-selected tagging SNPs across GRIK3 in three independent samples of Scandinavian origin from the Scandinavian Collaboration of Psychiatric Etiology (SCOPE), including a total of 839 cases with schizophrenia spectrum and 1473 healthy controls.Four markers (rs6671364, rs17461259, rs472188, and rs535620) attained nominally significant P-values in both the genotypic (0.002, 0.02, 0.03, and 0.05, respectively) and allelic (0.001, 0.006, 0.03, and 0.02, respectively) association tests for the combined sample, and 2 additional markers (rs481047and rs1160751) displayed significance for the genotype (P-values: 0.03 and 0.04). Several haplotypes, that all included at least one of the four SNPs implicated by the single marker analysis, remained significant after adjustment for multiple testing using permutations with 10,000 shuffles. In addition we observed an association for two of the four significant GRIK3 markers (rs472188 and rs535620) to scores for negative symptoms on the PANSS scale.The present results, although not robust, support the importance of more extensive investigations of GRIK3, given its potential role in mediating risk for schizophrenia.     

谷氨酸受体6基因多态与孤独症的关联分析

目的 在中国上海地区汉族孤独症家系中探讨谷氨酸受体6（GluR6或GRIK2）基因多态与孤独症是否关联。方法 采用PCR—RFLP法对入组的38个孤独症核心家系成员的GRIK2基因的两个单核苷酸多态性（rs6922753和rs2227283）分型,并进行传递不平衡检验。结果 rs6922753多态的C和T等位基因未发现显著性的偏移传递方式,rs2227283多态在母系传递中出现显著性的偏移,A等位基因较G等位基因传递明显增加。结论 GRIK2基因与孤独症存在传递的连锁不平衡,可能为孤独症的易感基因。     

No genetic association between polymorphisms in the kainate-type glutamate receptor gene, GRIK4, and schizophrenia in the Chinese population

BACKGROUND: Schizophrenia is a chronic psychiatric disorder with a strong genetic component. Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and that the kainate ionotropic glutamate receptors are involved in this mechanism. A recent study provides cytogenetic and genetic evidence to support a role for the kainate-type glutamate receptor gene (GRIK4), in schizophrenia. A systematic case-control association study of GRIK4 involving a Scottish population found that three SNPs, rs4935752, rs6589846 and rs4430518, were associated with schizophrenia. METHODS: Here, we investigated rs4935752, rs6589846, rs4430518 and other 2 SNPs within the GRIK4 gene in an association study of the Chinese population. Our sample consisted of 288 schizophrenia and 288 control subjects. All recruits were Han Chinese drawn from the city of Shanghai. RESULTS: No individual SNP nor any haplotype was associated with schizophrenia in our study. CONCLUSION: These results suggest that the five SNPs within the GRIK4 gene are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.     

Local gyrification index in patients with major depressive disorder and its association with tryptophan hydroxylase‐2 (TPH2) polymorphism

The tryptophan hydroxylase‐2 (TPH2) gene is considered a promising genetic candidate regarding its association with a predisposition to major depressive disorder (MDD). Local gyrification reflects the early neural development of cortical connectivity, and is regarded as a potential neural endophenotype in psychiatric disorders. They aimed to investigate the alterations in the cortical gyrification of the prefrontal cortex and anterior cingulate cortex and their association with the TPH2 rs4570625 polymorphism in patients with MDD. One hundred and thirteen patients with MDD and eighty‐six healthy controls underwent T1‐weighted structural magnetic resonance imaging and genotyping for TPH2 rs4570625. The local gyrification index of 22 cortical regions in the prefrontal cortex and anterior cingulate cortex was analyzed using the FreeSurfer. The patients with MDD showed significant hypergyria in the right rostral anterior cingulate cortex (P = 0.001), medial orbitofrontal cortex (P = 0.003), and frontal pole (P = 0.001). There was a significant genotype‐by‐diagnosis interaction for the local gyrification index in the right rostral anterior cingulate cortex (P = 0.003). Their study revealed significant hypergyria of the anterior cingulate cortex and prefrontal cortex and an interactive effect between the diagnosis of MDD and the genotype in the anterior cingulate cortex. This might be associated with the dysfunction of neural circuits mediating emotion processing, which could contribute to pathophysiology of MDD. Hum Brain Mapp 38:1299–1310, 2017. © 2016 Wiley Periodicals, Inc.     

Intrinsic functional and structural connectivity of emotion regulation networks in obsessive‐compulsive disorder

Despite emotion regulation being altered in patients with obsessive‐compulsive disorder (OCD), no studies have investigated its relation to multimodal amygdala connectivity. We compared corticolimbic functional and structural connectivity between OCD patients and healthy controls (HCs), and correlated this with the dispositional use of emotion regulation strategies and with OCD severity. OCD patients (n = 73) and HCs (n = 42) were assessed for suppression and reappraisal strategies using the Emotion Regulation Questionnaire (ERQ) and for OCD severity using the Yale‐Brown Obsessive‐Compulsive Scale. Resting‐state functional magnetic resonance imaging (rs‐fMRI) connectivity maps were generated using subject‐specific left amygdala (LA) and right amygdala (RA) masks. We identified between‐group differences in amygdala whole‐brain connectivity, and evaluated the moderating effect of ERQ strategies. Significant regions and amygdala seeds were used as targets in probabilistic tractography analysis. Patients scored higher in suppression and lower in reappraisal. We observed higher rs‐fMRI RA–right postcentral gyrus (PCG) connectivity in HC, and in patients this was correlated with symptom severity. Reappraisal scores were associated with higher negative LA–left insula connectivity in HC, and suppression scores were negatively associated with LA–precuneus and angular gyri connectivity in OCD. Structurally, patients showed higher mean diffusivity in tracts connecting the amygdala with the other targets. RA–PCG connectivity is diminished in patients, while disrupted emotion regulation is related to altered amygdala connectivity with the insula and posterior brain regions. Our results are the first showing, from a multimodal perspective, the association between amygdala connectivity and specific emotional processing domains, emphasizing the importance of amygdala connectivity in OCD pathophysiology.     

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain‐containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76‐CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.     

Common and rare alleles of the serotonin transporter gene,SLC6A4, associated with Tourette's disorder

To evaluate the hypothesis that functionally over‐expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT‐linked polymorphic region 5‐HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine‐to‐valine at position 425 (I425V). The higher expressing 5‐HTTLPR/rs25531 L_A allele was more prevalent in TD probands than in controls (χ² = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing L_AC haplotype (5‐HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14). Furthermore, the rare gain‐of‐function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family‐adjusted significance of χ² = 15.03 (P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society     

Transmission disequilibrium studies in children and adolescents with obsessive-compulsive disorders pertaining to polymorphisms of genes of the serotonergic pathway

Summary. Pharmacological and challenge study data showed an involvement of the serotonergic system in the development of obsessive-compulsive disorder (OCD). We studied transmission disequilibrium of polymorphisms in three candidate genes of the serotonergic pathway in 64 trios comprising patients with early onset OCD and both of their parents. Polymorphisms of the following genes were studied: tryptophan hydroxylase 1 (rs1800532), serotonin transporter (polymorphism in the promoter region; 5-HTTLPR) and the serotonin 1 B receptor (rs6296). This is, to our knowledge, one of the first family based association studies pertaining to children and adolescents with OCD. We did not detect transmission disequilibrium of the investigated polymorphisms in OCD. Hence, these polymorphisms do not play a major role in the genetic predisposition to early onset OCD.These authors contributed equally to this work     

LINGO1 polymorphisms are associated with essential tremor in Europeans

Essential tremor (ET) is one of the most common movement disorders. Former association studies focussing on candidate genes in ET found a number of risk variants but most of them were not replicated. Recently, a genome‐wide association study revealed two intronic sequence variants in the LINGO1 gene associated with ET. Here, we have confirmed association between sequence variants in the LINGO1 gene and the ET phenotype in independent German and French ET samples. The odds ratios for the identified intronic markers rs8030859 (P = 1.0×10^?4), rs9652490 (P = 9.1×10^?4), and rs11856808 (P = 3.6×10^?2) were 1.72 (CI 1.31‐2.26), 1.61 (CI 1.21‐2.14), and 1.30 (CI 1.02‐1.66), respectively, in our German sample. LINGO1 is an interesting candidate gene because it plays a key role in central nervous system biology, is selectively expressed in the nervous system, and is an inhibitor of oligodendrocyte differentiation and neuronal myelination. Our study gives further evidence that LINGO1 acts as a susceptibility gene for ET. © 2010 Movement Disorder Society     

Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A,DRD3 and SNAP-25 Genes

The results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25 KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine β-hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results.     

Association of intronic polymorphism rs3773364 A>G in synapsin‐2 gene with idiopathic epilepsy

In epilepsy, there is a tendency towards recurrent unprovoked seizures. Seizures result due to the excessive electrical misfiring in the brain between neurons and disturbance in neurotransmitter release. Several gene products affect the behavior of these neurons by regulating neurotransmission via several mechanisms. One such gene, Synapsin‐2 (SYN2), involved in synaptogenesis is also reported to regulate the neurotransmitter release. We hypothesized that SYN2 gene and its polymorphisms could affect the process of epileptogenesis and therapeutic response in humans. In this hospital‐based study, we enrolled 372 patients with epilepsy and 199 control subjects. We selected rs3773364 A>G polymorphism in SYN2 gene and analyzed its distribution in north Indian patients with epilepsy and control subjects. Genotyping was carried out by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. According to the results obtained, SYN2 “AG” genotype frequency was significantly higher in patients with epilepsy versus control subjects in north Indian population (P = 0.02, OR = 1.55, 95% CI = 1.06–2.26). After subclassification, we observed higher frequency of AG genotype in idiopathic patients as compared to control subjects (P = 0.01, OR = 1.67, 95% CI = 1.08–2.56). There were no significant differences in genotypic (AG: OR = 0.80, P = 0.377; GG: P = 0.628, OR = 1.17) or allelic (P = 0.86, OR = 1.03) frequency distributions in patients with multiple drug resistance versus patients with drug‐responsive epilepsy. Results from our study indicate the involvement of SYN2 gene polymorphism in conferring risk to epilepsy; however, the genetic variant does not seem to modulate drug‐response in epilepsy pharmacotherapy. Synapse 64:403–408, 2010. © 2009 Wiley‐Liss, Inc.     

−141C insertion/deletion polymorphism of the dopamine D2 receptor gene is associated with schizophrenia in Chinese Han population: Evidence from an ethnic group‐specific meta‐analysis

Accumulate evidence has implicated dopamine D2 receptor gene polymorphisms in the etiology of schizophrenia. A single nucleotide polymorphism, ?141C insertion/deletion (Ins/Del) (rs1799732), in the promoter region of the dopamine D2 receptor gene has been linked to schizophrenia; however, the data are inconclusive. This study investigated whether the ?141C polymorphism is associated with the risk of schizophrenia in different ethnic groups by performing a meta‐analysis. A total of 24 case–control studies examining the association between ?141C Ins/Del polymorphism and schizophrenia were identified according to established inclusion criteria. Significant association was revealed between ?141C Ins/Del polymorphism and schizophrenia risk in dominant genetic model (Ins/Ins + Ins/Del versus Del/Del) (odds ratio = 0.33, 95% confidence interval = 0.14–0.81, z = 2.41, P = 0.02) in Chinese Han but not in Caucasian, Japanese or India populations. Our results indicate that ?141C Ins/Del polymorphism might be a susceptibility factor for schizophrenia in Chinese Han population.     

Association Study of Brain-Derived Neurotrophic Factor Gene Polymorphisms and Body Weight Change in Schizophrenic Patients Under Long-Term Atypical Antipsychotic Treatment

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.     

The NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism

Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Jinde S, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N. The NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism. Objective: Autism appears to have a strong genetic component. The product of the NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene is included in the mitochondrial electron transport chain. Method: We performed a case–control study of 235 patients with autism and 214 controls and examined three single‐nucleotide polymorphisms (SNPs) within this gene in a Japanese population. We then conducted a transmission disequilibrium test (TDT) analysis in 148 autistic trios. Results: In the case–control study, two SNPs (rs12666974 and rs3779262) showed a significant association with autism (P = 0.00064 and 0.00046 respectively). Furthermore, a haplotype containing these two SNPs showed a significant association (P‐global = 0.0013, individual haplotype A‐A : P = 0.010). In TDT analysis, the global and A‐A haplotype P‐values also indicated significant associations. Minor allele and genotype frequencies were decreased in the autistic subjects. Conclusion: We found significant association between the NDFA5 gene and autism.