Paul D. Arnold

Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive-Compulsive Disorder

A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The L(G) allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and L(G) alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function L(A)L(A) genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The L(A) allele was twofold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.

Rare Copy Number Variation Discovery and Cross-Disorder Comparisons Identify Risk Genes for ADHD

A high-resolution analysis of copy number variation in patients with ADHD reveals new gene associations, few de novo mutations, and overlap with genes implicated in other disorders such as autism. Complexities of Cognition: The Case of ADHD As for autism and schizophrenia, the closer we look at attention deficit hyperactivity disorder (ADHD), the more complicated it seems. Found in 4% of children, this syndrome of attention, hyperactivity, and impulsiveness is highly heritable, yet we know only a few of the responsible genetic variants. Here, Lionel et al. assessed a particularly well-defined population of 248 children with ADHD, plus many of their parents, for extra copies or deletions of genes. The 306 rare copy number variations (CNVs) found in these individuals were of various kinds—only 1.7% were de novo mutations in brain-specific genes, 7.7% were clearly inherited and occurred in genes known to be associated with ADHD or defined new culprit genes, and several were in genes already implicated in other disorders such as autism. To take a closer look at possible genes that confer risk for more than one developmental disorder, the authors examined the CNVs in a separate group of patients with autism. In four autism patients and two of the patients with ADHD, a cluster of rare disorder-associated CNVs occurred on chromosome 9 in and around two genes: ASTN2, necessary for mammalian brain development, and TRIM32, a neuronal stem cell–associated gene. This region has also been associated with CNVs in bipolar disorder, intellectual disability, and schizophrenia. In all, the authors found rare inherited CNVs at sites that had been previously implicated in ADHD or in other neurodevelopmental disorders in 8% of the individuals with ADHD. Their results implicate common genes and pathways for several neuropsychiatric disorders, which is consistent with the common clinical co-occurrence of ADHD with other such conditions. Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.

Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.

RationaleRecent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl-d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3′ untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl-d-aspartate 2B) were associated with OCD in affected families.ObjectivesThe objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design.MethodsUsing the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity.ResultsUnder a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested (P=0.014). In addition, there was a significant positive association with OCD diagnosis (P=0.002) for the 5072G–5988T haplotype under the recessive model.ConclusionsAlthough preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. While the neurobiology and etiology of OCD has not been fully elucidated, there is growing evidence that disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical (CSTC) circuitry plays a role in OCD pathogenesis. This review summarizes the findings from neuroimaging, animal model, candidate gene and treatment studies in the context of glutamate signaling dysfunction in OCD. First, studies using magnetic resonance spectroscopy are reviewed demonstrating altered glutamate concentrations in the caudate and anterior cingulate cortex of patients with OCD. Second, knockout mouse models, particularly the DLGAP3 and Sltrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling dysfunction. Third, candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 which has been shown to be associated with OCD in five independent studies. This converging evidence for a role of glutamate in OCD has led to the development of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine. We conclude the review by outlining a glutamate hypothesis for OCD, which we hope will inform further research into etiology and treatment for this severe neuropsychiatric condition.

The optimal radiologic method for assessing spinal canal compromise and cord compression in patients with cervical spinal cord injury. Part II : Results of a multicenter study

STUDY DESIGN A multicenter, retrospective study using computed tomographic and magnetic resonance imaging data to establish quantitative, reliable criteria of canal compromise and cord compression in patients with cervical spinal cord injury. OBJECTIVES To develop and validate a radiologic assessment tool of spinal canal compromise and cord compression in cervical spinal cord injury for use in clinical trials. SUMMARY OF BACKGROUND DATA There are few quantitative, reliable criteria for radiologic measurement of cervical spinal canal compromise or cord compression after acute spinal cord injury. METHODS The study included 71 patients (55 men, 16 women; mean age, 39.7 +/- 18.7 years) with acute cervical spinal cord injury. Causes of spinal cord injury included motor vehicle accidents (n = 36), falls (n = 20), water-related injuries (n = 8), sports (n = 5), assault (n = 1), and farm accidents (n = 1). Canal compromise was measured on computed tomographic scan and T1- and T2-weighted magnetic resonance imaging, and cord compression at the level of maximum injury was measured on T1- and T2-weighted magnetic resonance imaging. All films were assessed by two independent observers. RESULTS There was a strong correlation of canal compromise and/or cord compression measurements between axial and midsagittal computed tomography, and between axial and midsagittal T2-weighted magnetic resonance imaging. Spinal canal compromise assessed by computed tomography showed a significant although moderate correlation with spinal cord compression assessed by T1- and T2-weighted magnetic resonance imaging. Virtually all patients with canal compromise of 25% or more on computed tomographic scan had evidence of some degree of cord compression on magnetic resonance imaging, but a large number of patients with less than 25% canal compromise on computed tomographic scan also had evidence on magnetic resonance imaging of cord compression. CONCLUSIONS In patients with cervical spinal cord injury, the midsagittal T1- and T2-weighted magnetic resonance imaging provides an objective, quantifiable, and reliable assessment of spinal cord compression that cannot be adequately assessed by computed tomography alone.

Injury of the posterior ligamentous complex of the thoracolumbar spine: a prospective evaluation of the diagnostic accuracy of magnetic resonance imaging.

Study Design. Prospective diagnostic imaging study. Objective. To determine the accuracy of magnetic resonance imaging (MRI) in diagnosing injury of the posterior ligamentous complex (PLC) in patients with thoracolumbar trauma. Summary of Background Data. Treatment decisions in thoracolumbar injury patients are currently based on the status of the PLC. It is, therefore, important to understand the accuracy of MRI in diagnosing varying degrees of PLC injury. Prior studies report that MRI is up to 100% sensitive for diagnosing PCL injury. Methods. Patients with an acute injury from T1 to L3 who required posterior surgery were prospectively studied. A musculoskeletal radiologist, based on the preoperative MRI findings, characterized each of the 6 components of the PLC as intact, incompletely disrupted, or disrupted. During the surgical procedure, the surgeon identified each component of the PLC as intact, incompletely disrupted, or disrupted. The radiologists interpretation and surgical findings were compared. Results. Forty-two patients with 62 levels of injury were studied. There were 33 males (78.6%) and 9 females (21.4%), and the average age was 35.7 years. According to the kappa score, there was a moderate level of agreement between the radiologists interpretation and the intraoperative findings for all PLC components except the thoracolumbar fascia, for which there was slight agreement. The sensitivity for the various PLC components ranged from 79% (left facet capsule) to 90% (interspinous ligament). The specificity ranged from 53% (thoracolumbar fascia) to 65% (ligamentum flavum). There was less agreement between the radiologist and surgeon for the patients with less severe neurologic compromise, i.e., those patients with an AIS grade of either D or E. Conclusion. The sensitivity and specificity of MRI for diagnosing injury of the PLC are lower than previously reported in the literature. The integrity of the PLC as determined by MRI should not be used in isolation to determine treatment.

Overview of genetics and obsessive-compulsive disorder

This paper reviews the current state of research into the genetics of obsessive-compulsive disorder (OCD). Heredity has a major role in OCD etiology. This evidence comes from several methodological approaches such as family, twin, and segregation analysis studies. A major single gene effect as well as a polygenic hypothesis has been suggested based on segregation studies. In addition, candidate gene association and linkage analyses have shown not only one gene, but a few interesting genes and areas of the genome that may be relevant in OCD. In this search for genes, new definitions of the OCD phenotype have emerged, and some of them may be considered intermediate phenotypes between the gene effect and OCD-DSM-IV diagnosis. The phenotypic and genetic heterogeneity of OCD magnifies the challenge of locating susceptibility genes; at the same time, the identification of vulnerability genes will elucidate the identification of subtypes or dimensions of the disorder. Therefore research strategies that take advantage of clinical subtyping and that redefine the OCD phenotype in the context of genetic studies may potentially contribute to the nosology of OCD and ultimately pathophysiology. There is a lack of understanding about how genes and environment interact in OCD. However, there are some reports that will be discussed, which have attempted to evaluate how the environment contributes to OCD.

Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive-compulsive disorder

In this preliminary study, 16 psychotropic-naïve pediatric patients with obsessive-compulsive disorder (OCD) were studied using magnetic resonance spectroscopy (MRS) and genotyped for six candidate polymorphisms in two glutamate system genes. A significant association was identified between the rs1019385 polymorphism of the glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and decreased anterior cingulate cortex (ACC) glutamatergic concentration (Glx) but not with occipital Glx. These results suggest that GRIN2B may be associated with Glx in the ACC, a region consistently implicated in OCD.

Evidence for the gamma‐amino‐butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive‐compulsive disorder

Obsessive‐compulsive disorder (OCD) is a well‐recognized severe neuropsychiatric illness. Genetic factors are believed to be important etiologically. Although historically genetic testing has focused on the serotonergic and dopaminergic systems, there is increasing evidence that the major inhibitory neurotransmitter, gamma‐aminobutyric acid (GABA), may also be functionally involved. Furthermore the GABA type B receptor 1 (GABBR1) gene has been localized to chromosome 6p21.3 region, which has shown linkage to OCD. We investigated five polymorphisms (A–7265G substitution; C10497G substitution; A33795G substitution in the 3′‐UTR; Ser‐491‐Ser‐T1473C transition; Phe‐659‐Phe‐T1977C transition) in the GABBR1 gene in a sample of 159 DSM‐IV OCD probands and their families, using the transmission disequilibrium test (TDT). A trend was observed with an over‐transmission of −7265A allele at the A‐7265G polymorphism and OCD (χ2 = 3.270, P = 0.071). Moreover, the TDT haplotype analysis using TRANSMIT showed a trend toward association with the haplotype of the five polymorphisms together [2.1.1.2.1 (A‐7265G.C10497G.Ser‐491‐Ser.Phe‐659‐Phe.A33795G)] with a Chi‐square value of 3.418, which corresponds to a P‐value of 0.065 (overall χ2 = 6.353, 5 df, P = 0.273). Moreover, a trend was observed for the total Yale‐Brown obsessive‐compulsive scale score in the A‐7265G polymorphism (−7265A: z = 1.934, P = 0.053) using the Family‐Based Association Test, considering the diagnosis of OCD and then the clinically relevant quantitative phenotypes. The observed trends suggest that further investigations of the role of the GABBR1 gene in OCD are warranted.

Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder

Obsessive‐compulsive disorder (OCD) is a severe neuropsychiatric disorder with a strong genetic component, and may involve autoimmune processes. Support for this latter hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), with onset of OCD symptoms following streptococcal infections. Genes involved in immune response therefore represent possible candidate genes for OCD, including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune system. Four polymorphisms in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat (MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were investigated for the possibility of association with OCD using 160 nuclear families with an OCD proband. We examined the transmission of alleles of these four polymorphisms with the transmission disequilibrium test (TDT). A biased transmission of the 459‐bp allele (allele 2: χ2 = 5.255, P = 0.022) of MOG4 was detected, while MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype 1.13.2.2 (χ2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the family‐based association test (FBAT) was significant for MOG4 in total Yale‐Brown Obsessive‐Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further investigations combining genetic, pathological, and pharmacological strategies, are warranted.