[show abstract][hide abstract] ABSTRACT: The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
[show abstract][hide abstract] ABSTRACT: The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.European Journal of Human Genetics advance online publication, 16 January 2013; doi:10.1038/ejhg.2012.245.
European journal of human genetics: EJHG 01/2013; · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Family studies have consistently shown that Tourette syndrome (TS) is a familial disorder and twin studies have clearly indicated a genetic contribution in the etiology of TS. Whereas early segregation studies of TS suggested a single-gene autosomal dominant disorder, later studies have pointed to more complex models including additive and multifactorial inheritance and likely interaction with genetic factors. While the exact cellular and molecular base of TS is as yet elusive, neuroanatomical and neurophysiological studies have pointed to the involvement of cortico-striato-thalamocortical circuits and abnormalities in dopamine, glutamate, gamma-aminobutyric acid, and serotonin neurotransmitter systems, with the most consistent evidence being available for involvement of dopamine-related abnormalities, that is, a reduction in tonic extracellular dopamine levels along with hyperresponsive spike-dependent dopamine release, following stimulation. Genetic and gene expression findings are very much supportive of involvement of these neurotransmitter systems. Moreover, intriguingly, genetic work on a two-generation pedigree has opened new research pointing to a role for histamine, a so far rather neglected neurotransmitter, with the potential of the development of new treatment options. Future studies should be aimed at directly linking neurotransmitter-related genetic and gene expression findings to imaging studies (imaging genetics), which enables a better understanding of the pathways and mechanisms through which the dynamic interplay of genes, brain, and environment shapes the TS phenotype.
International Review of Neurobiology 01/2013; 112:155-77. · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.Molecular Psychiatry advance online publication, 14 August 2012; doi:10.1038/mp.2012.69.
[show abstract][hide abstract] ABSTRACT: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes.
We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated.
While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10(-4) - 1.6 × 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes.
We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
[show abstract][hide abstract] ABSTRACT: Recent studies have provided much needed data on the probability of seizure remission among adults with chronic intractable epilepsy treated medically. Here we provide an extended follow-up to our earlier study in order to provide a more comprehensive picture of long-term prognosis in this patient population during medical treatment. The prevalence cohort was followed for two outcomes-complete seizure remission for ≥ 12 months and subsequent seizure relapse among those attaining a seizure remission. The study outcomes were estimated using Kaplan-Meier analysis. We found that the probability of attaining a ≥ 12 months of complete seizure freedom to be approximately 3-4% per year through 8 years of follow-up. By year 5 since the start of seizure remission, the cumulative probability of seizure relapse was 81%, although only half of the patients with seizure relapse went on to experience their previous seizure frequency.
Epilepsy research 02/2011; 93(2-3):115-9. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Dadd et al. [Hum Hered 2010;69:285-294] recently criticized our delta-centralization (DC) method of controlling for population stratification (PS) and concluded that DC does not work. To explore our method, the authors simulated data under the Balding-Nichols (BN) model, which is more general than the model we had used in our simulations. They determined that the DC method underestimated the PS parameter (δ) and inflated the type I error rates when applied to BN-simulated data, and from this they concluded that the DC method is invalid. However, we argue that this conclusion is premature. In this paper, we (1) show why δ is underestimated and type I error rates are inflated when BN-simulated data are used, and (2) present a simple adjustment to DC that works reasonably well for data from both kinds of simulations. We also show that the adjusted DC method has appropriate power under a range of scenarios.
Human Heredity 01/2011; 71(3):180-5. · 1.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with epilepsy are frequently confronted with complex treatment decisions. Communicating treatment risks is often difficult because patients may have difficulty with basic statistical concepts (i.e., low numeracy) or might misconceive the statistical information based on the way information is presented, a phenomenon known as "framing bias." We assessed numeracy and framing bias in 95 adults with chronic epilepsy and explored cognitive correlates of framing bias. Compared with normal controls, patients with epilepsy had significantly poorer performance on the Numeracy scale (P=0.02), despite a higher level of education than normal controls (P<0.001). Compared with patients with higher numeracy, patients with lower numeracy were significantly more likely to exhibit framing bias. Abstract problem solving performance correlated with the degree of framing bias (r=0.631, P<0.0001), suggesting a relationship between aspects of executive functioning and framing bias. Poor numeracy and susceptibility framing bias place patients with epilepsy at risk for uninformed decisions.
[show abstract][hide abstract] ABSTRACT: Depression is the most common comorbid condition in epilepsy. The cause of this comorbidity is unknown, and could involve psychosocial consequences of epilepsy, treatment side effects, seizure manifestations, or common neurobiologic mechanisms. One hypothesis of particular interest is a shared genetic susceptibility to epilepsy and depression. We tested this hypothesis by studying depressive symptoms in families with an identified genetic form of epilepsy: autosomal dominant partial epilepsy with auditory features caused by mutations in the leucine-rich, glioma inactivated 1 gene (LGI1).
A standardized depression screen was administered to 94 individuals from 11 families with mutations in LGI1, including 38 mutation carriers with epilepsy (AC), 11 clinically unaffected mutation carriers (UC), and 45 noncarriers (NC).
Current depressive symptom scores were significantly higher in AC than in NC, an association that remained after excluding depressive symptoms that appeared likely to be caused by antiepileptic medication use. However, scores did not differ between UC and NC.
Although LGI1 mutation carriers who were clinically affected with epilepsy had increased depressive symptoms, mutation carriers without epilepsy did not. These findings suggest that the increase in depressive symptoms in affected individuals from these families is related to epilepsy or its treatment rather than to LGI1 mutations per se.
[show abstract][hide abstract] ABSTRACT: Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.
New England Journal of Medicine 05/2010; 362(20):1901-8. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Abeta toxicity. Towards this goal, we generated Abeta transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Abeta and increased lifespan in Abeta flies, whereas loss of function of FKBP52 exacerbated these Abeta phenotypes. Interestingly, the Abeta pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (-/-) cells have increased intracellular copper and higher levels of Abeta. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Abeta peptides.
PLoS ONE 01/2010; 5(1):e8626. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: We examined whether duration of epilepsy prior to temporal lobe resection has decreased over the years as a result of increasing body of evidence in the literature showing the benefits of anterior temporal resection. We stratified the 213 patients, who had their first temporal lobe resection at our center between 1996 and 2007 into three groups in order to detect any trends in duration of epilepsy: group A (surgery between 1996 and 1999); group B (surgery between 2000 and 2003); group C (surgery between 2004 and 2007). No difference in mean duration of epilepsy was detected between the three groups (p=0.54). The mean duration in epilepsy prior to temporal lobe resection has persisted at greater than 20 years during the past two decades.
Epilepsy research 08/2009; 86(2-3):224-7. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia.
We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed.
Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found.
Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected.
Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.
The Lancet Neurology 05/2009; 8(5):441-6. · 23.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is comorbidity and a possible genetic connection between Bipolar disease (BP) and panic disorder (PD). Genes may exist that increase risk to both PD and BP. We explored this possibility using data from a linkage study of PD (120 multiplex families; 37 had > or =1 BP member). We calculated 2-point lodscores maximized over male and female recombination fractions by classifying individuals with PD and/or BP as affected (PD + BP). Additionally, to shed light on possible heterogeneity, we examine the pedigrees containing a bipolar member (BP+) separately from those that do not (BP-), using a Predivided-Sample Test (PST). Linkage evidence for common genes for PD + BP was obtained on chromosomes 2 (lodscore = 4.6) and chromosome 12 (lodscore = 3.6). These locations had already been implicated using a PD-only diagnosis, although at both locations this was larger when a joint PD + BP diagnosis was used. Examining the BP+ families and BP- families separately indicates that both BP+ and BP- pedigrees are contributing to the peaks on chromosomes 2 and 12. However, the PST indicates different evidence of linkage is obtained from BP+ and BP- pedigrees on chromosome 13. Our findings are consistent with risk loci for the combined PD + BP phenotype on chromosomes 2 and 12. We also obtained evidence of heterogeneity on chromosome 13. The regions on chromosomes 12 and 13 identified here have previously been implicated as regions of interest for multiple psychiatric disorders, including BP.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2009; 150B(8):1139-46. · 3.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tourette Syndrome is a neuropsychiatric disorder characterized by chronic motor and phonic tics. Affected individuals and their family members are at an increased risk for other neuropsychiatric conditions including obsessive-compulsive disorder and attention deficit hyperactivity disorder. While there is consistent evidence that genetic factors play a significant etiologic role, no replicable susceptibility alleles have thus far been identified.
Here we discuss a sharing resource of clinical and genetic data, the New Jersey Center for Tourette Syndrome Sharing Repository, whose goal is to provide clinical data, DNA, and lymphoblastoid cell lines to qualified researchers.
Opening access to the data and patient material to the widest possible research community will hasten the identification of causal genetic factors and facilitate better understanding and treatment of this often impairing disorder.
BMC Medical Genomics 12/2008; 1:58. · 3.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the cumulative probabilities of >or=12 month seizure remission and seizure relapse following remission, and to test the associations of clinical characteristics with these two study end points in a prevalence cohort of intractable adult epilepsy patients during medical management.
A retrospective cohort study of intractable epilepsy patients seen in 2001 at a single center was conducted. Kaplan-Meier analysis was used to estimate the cumulative probabilities of seizure remission and subsequent seizure relapse. Cox proportional hazards models were used to estimate the association (1) between clinical factors and >or=12 month seizure remission and (2) between clinical factors and seizure relapse following remission.
One hundred eighty-seven subjects met the eligibility criteria for intractable epilepsy. The estimate of probability of remission was about 4% per year. Seizure remission was temporary for some individuals, as 5 out of 20 subjects with remission ultimately relapsed. No clinical factors predicted the likelihood of achieving >or=12 month seizure remission or subsequent seizure relapse.
Some people with intractable epilepsy achieve >or=12 month seizure remission during medical treatment. Remission, however, is only temporary for some individuals. We were unable to identify clear predictors for remission.