Reid J. Robison

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.

We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.

Genome-wide linkage in Utah autism pedigrees

Genetic studies of autism over the past decade suggest a complex landscape of multiple genes. In the face of this heterogeneity, studies that include large extended pedigrees may offer valuable insights, as the relatively few susceptibility genes within single large families may be more easily discerned. This genome-wide screen of 70 families includes 20 large extended pedigrees of 6–9 generations, 6 moderate-sized families of 4–5 generations and 44 smaller families of 2–3 generations. The Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina Linkage Panel 12, a 6K single-nucleotide polymorphism (SNP) platform. Results from 192 subjects with an autism spectrum disorder (ASD) and 461 of their relatives revealed genome-wide significance on chromosome 15q, with three possibly distinct peaks: 15q13.1–q14 (heterogeneity LOD (HLOD)=4.09 at 29 459 872 bp); 15q14–q21.1 (HLOD=3.59 at 36 837 208 bp); and 15q21.1–q22.2 (HLOD=5.31 at 55 629 733 bp). Two of these peaks replicate earlier findings. There were additional suggestive results on chromosomes 2p25.3–p24.1 (HLOD=1.87), 7q31.31–q32.3 (HLOD=1.97) and 13q12.11–q12.3 (HLOD=1.93). Affected subjects in families supporting the linkage peaks found in this study did not reveal strong evidence for distinct phenotypic subgroups.

Methylphenidate Transdermal System in Adult ADHD and Impact on Emotional and Oppositional Symptoms.

Objective: This trial evaluated the effect of methylphenidate transdermal system (MTS) on the full spectrum of adult symptoms (attention-disorganization, hyperactivity-impulsivity, emotional dysregulation [ED], and oppositional-defiant disorder [ODD]) found in this disorder. Method: This placebo-controlled, double-blind, flexible-dose, crossover trial employed the Wender—Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) and Connor’s Adult ADHD Rating Scale (CAARS) and two measures of adult ODD. Treatment responses of all participants and four subgroups (ADHDalone, ADHD + ED, ADHD + ODD, and ADHD + ED + ODD) were assessed. Results: Around 23% of baseline participants were ADHD alone, 31% were ADHD + ED, 10% were ADHD + ODD, and 36% were ADHD + ED + ODD. There was a significant treatment effect for all symptom areas and all four subgroups. MTS was associated with significantly more adverse events, especially dermatologic side effects. Conclusions: MTS was effective in treating adult ADHD. This clinical trial included numerous participants meeting criteria for ED and ODD. All ADHD symptoms responded positively to treatment with MTS.

Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees

BackgroundAutism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability.MethodsWe present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees.ResultsWhen analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19.ConclusionsThe SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.

SeqHBase: a big data toolset for family based sequencing data analysis

Background Whole-genome sequencing (WGS) and whole-exome sequencing (WES) technologies are increasingly used to identify disease-contributing mutations in human genomic studies. It can be a significant challenge to process such data, especially when a large family or cohort is sequenced. Our objective was to develop a big data toolset to efficiently manipulate genome-wide variants, functional annotations and coverage, together with conducting family based sequencing data analysis. Methods Hadoop is a framework for reliable, scalable, distributed processing of large data sets using MapReduce programming models. Based on Hadoop and HBase, we developed SeqHBase, a big data-based toolset for analysing family based sequencing data to detect de novo, inherited homozygous, or compound heterozygous mutations that may contribute to disease manifestations. SeqHBase takes as input BAM files (for coverage at every site), variant call format (VCF) files (for variant calls) and functional annotations (for variant prioritisation). Results We applied SeqHBase to a 5-member nuclear family and a 10-member 3-generation family with WGS data, as well as a 4-member nuclear family with WES data. Analysis times were almost linearly scalable with number of data nodes. With 20 data nodes, SeqHBase took about 5 secs to analyse WES familial data and approximately 1 min to analyse WGS familial data. Conclusions These results demonstrate SeqHBases high efficiency and scalability, which is necessary as WGS and WES are rapidly becoming standard methods to study the genetics of familial disorders.

Oppositional Defiant Disorder in Adults With ADHD

Objective: Oppositional defiant disorder (ODD) is the most common comorbid condition in childhood ADHD. This trial was prospectively designed to explore ODD symptoms in ADHD adults. Method: A total of 86 patients in this placebo-controlled, double-blind trial of methylphenidate transdermal system (MTS) were categorized based on the presence of ODD symptoms in childhood and adulthood, and then were compared for baseline and outcome differences. Results: In all, 42% met Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria for ODD as adults and were significantly more impaired on measures of ADHD, personality disorder, and substance abuse and 27% had childhood ODD that had resolved. Childhood and adult ODD symptoms were significantly correlated. ODD and ADHD symptoms improved significantly with MTS (p < .001), and the most consistently significant results were found in participants with adult ODD. Conclusion: A total of 69% met criteria for ODD as children and/or adults. Understanding how ODD interacts with ADHD to impact personality disorder, substance abuse, and treatment response has important clinical, social, and theoretical implications.

A unified theory of autism revisited: linkage evidence points to chromosome X using a high-risk subset of AGRE families.

Zhao et al. [ 2007 ] in their “Unified Theory of Autism” hypothesized that incidence of autism in males could be explained by essentially two types of family structures: majority of autism cases are from low‐risk autism families with de novo mutations, and a minority of cases are from high‐risk multiplex families, where risk to male offspring approximates 50% consistent with a dominant model and high penetrance. Using the Autism Genetic Resource Exchange (AGRE) data set, Zhao et al. identified 86 high‐risk families with likely dominant transmission. As genotype data are now available for many members of the AGRE resource, the objective of this manuscript was to determine if dominant linkage evidence for an autism predisposition gene exists in these 86 high‐risk families. HumanHap550K Illumina SNP data were available for 92% of 455 total family members in these 86 high‐risk families. We performed a linkage analysis using a pruned subset of markers where markers in high linkage disequilibrium were removed. We observed a single suggestive peak (maximum LOD 2.01, maximum HLOD 2.08) under a dominant model on chromosome Xp22.11‐p21.2 that encompasses the IL1RAPL1 gene. Mutations or deletions in IL1RAPL1 have been previously reported in three families with autism. In our study, 11 families contributed nominally (P<0.05, HLOD>0.588) to the chromosome X peak. These results demonstrate that identification of a more homogeneous subset of autism cases, which was based on family structure in this study, may help to identify, localize and further our understanding of autism predisposition genes.

Integrating precision medicine in the study and clinical treatment of a severely mentally ill person

Background. In recent years, there has been an explosion in the number of technical and medical diagnostic platforms being developed. This has greatly improved our ability to more accurately, and more comprehensively, explore and characterize human biological systems on the individual level. Large quantities of biomedical data are now being generated and archived in many separate research and clinical activities, but there exists a paucity of studies that integrate the areas of clinical neuropsychiatry, personal genomics and brain-machine interfaces. Methods. A single person with severe mental illness was implanted with the Medtronic Reclaim® Deep Brain Stimulation (DBS) Therapy device for Obsessive Compulsive Disorder (OCD), targeting his nucleus accumbens/anterior limb of the internal capsule. Programming of the device and psychiatric assessments occurred in an outpatient setting for over two years. His genome was sequenced and variants were detected in the Illumina Whole Genome Sequencing Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Results. We report here the detailed phenotypic characterization, clinical-grade whole genome sequencing (WGS), and two-year outcome of a man with severe OCD treated with DBS. Since implantation, this man has reported steady improvement, highlighted by a steady decline in his Yale-Brown Obsessive Compulsive Scale (YBOCS) score from ∼38 to a score of ∼25. A rechargeable Activa RC neurostimulator battery has been of major benefit in terms of facilitating a degree of stability and control over the stimulation. His psychiatric symptoms reliably worsen within hours of the battery becoming depleted, thus providing confirmatory evidence for the efficacy of DBS for OCD in this person. WGS revealed that he is a heterozygote for the p.Val66Met variant in BDNF, encoding a member of the nerve growth factor family, and which has been found to predispose carriers to various psychiatric illnesses. He carries the p.Glu429Ala allele in methylenetetrahydrofolate reductase (MTHFR) and the p.Asp7Asn allele in ChAT, encoding choline O-acetyltransferase, with both alleles having been shown to confer an elevated susceptibility to psychoses. We have found thousands of other variants in his genome, including pharmacogenetic and copy number variants. This information has been archived and offered to this person alongside the clinical sequencing data, so that he and others can re-analyze his genome for years to come. Conclusions. To our knowledge, this is the first study in the clinical neurosciences that integrates detailed neuropsychiatric phenotyping, deep brain stimulation for OCD and clinical-grade WGS with management of genetic results in the medical treatment of one person with severe mental illness. We offer this as an example of precision medicine in neuropsychiatry including brain-implantable devices and genomics-guided preventive health care.