Whole-exome sequencing identifies genes associated with Tourette’s disorder in multiplex families

Tourette’s Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein–protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.This study was supported by a grant from the National Institute of Mental Health (R01MH092293 to GAH and JAT) and by a grant from the New Jersey Center for Tourette Syndrome (to GAH and JAT). This study was also supported by grants from the National Institute of Mental Health (K08MH099424 to TVF) and the National Institute for Environmental Health Science (R01 ES021462 for YSK and BLL). PM has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña, and the Jaques and Gloria Gossweiler Foundation. AM has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. AM has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1, and FOR 2698). AJW received a Young Investigator Award from Tourette Association of America. IH declares that all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre

Investigation of gene–environment interactions in relation to tic severity

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.This research was funded by National Institute of Mental Health (NIMH) grant R01MH092293 (to GAH and JAT) and NJCTS (New Jersey Center for Tourette Syndrome and Associated Disorders; to GAH and JAT). This work was also supported by grants from the Judah Foundation, the Tourette Association of America, National Institute of Health (NIH) Grants NS40024, NS016648, MH079489, MH073250, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1; NS16648-29S1; NS040024-09S1; MH092289; MH092290; MH092291; MH092292; R01MH092293; MH092513; MH092516; MH092520; MH071507; MH079489; MH079487; MH079488; and MH079494. Dr. Mir has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Dr. Morer has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. Dr. Münchau has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1 and FOR 2698). This study was also supported by a Grant from the National Institute for Environmental Health Science (R01 ES021462)

Activation in Children and Adolescents Treated With Selective Serotonin Reuptake Inhibitors: A Weighty Reason?

Activation is a behavioral adverse event related to the use of psychotropic medication. Its high incidence in pediatrics and in childhood-onset neuropsychiatric disorders suggests it may be linked to neurodevelopment. However, previous studies have scarcely examined the role that factors relevant to developmental pharmacokinetics, such as body weight, may play in the onset of activation in children and adolescents. We conducted a retrospective analysis of hospitalized patients to identify the risk factors for activation in children and adolescents treated with selective serotonin reuptake inhibitors. Our focus was on factors related to development, including body weight, to explore the relationship between activation and neurodevelopmental processes. Among the 139 participants (mean age, 14 ± 2.3 years), activation appeared in 29 (20.9%). Age 12 years or younger and comorbid diagnosis of autism spectrum disorder were associated with statistically significant increases in the risk of activation, but no association was found regarding body weight. Our findings support the hypothesis that activation is closely linked to brain development processes. Longitudinal studies are needed to explore this line of research further

Trastornos de tics e impulso premonitorio: validación de la versión española de la «Escala para el Impulso Premonitorio al Tic» en niños y adolescentes

[Introduction] Most people with persistent tics report an unpleasant sensation (premonitory urge) before the tic. In recent years, interest in these sensory phenomena has increased due to their important role in behavioural therapy. However, instruments for assessing these sensations remain scarce. Among the available instruments, the Premonitory Urge for Tics Scale (PUTS) is the most widely used.[Methods] We examined the psychometric properties and factor structure of the Spanish-language version of the PUTS in a sample of 72 children and adolescents with Tourette syndrome or persistent tic disorders. We analysed data from the total sample and by age group (children up to 10 years old and children/adolescents over 10).[Results] The PUTS presented good internal consistency and moderate correlations between items on the scale (except for item one). Divergent validity was good, test-retest reliability was adequate, and a bifactorial structure was identified (one dimension related to mental phenomena reported in obsessive-compulsive disorder, and another related to the quality and frequency of premonitory urges). These results were replicated in both age groups, with lower divergent validity and test-retest reliability in the younger group.[Conclusions] The Spanish-language version of the PUTS is a valid, reliable tool for assessing premonitory urges in both children and adolescents, especially after the age of 10.[Introducción] La mayoría de personas con tics persistentes refiere notar una sensación desagradable (impulso premonitorio) antes de sufrir un tic. En los últimos años, el interés hacia estos fenómenos sensoriales ha aumentado debido al importante papel que tienen en la terapia de conducta. Sin embargo, los instrumentos para evaluarlos aún son escasos. Entre ellos, la Escala para el Impulso Premonitorio al Tic (Premonitory Urge for Tics Scale, PUTS) es el más utilizado.[Métodos] Examinamos las propiedades psicométricas y la estructura factorial de la versión española de la PUTS en una muestra de 72 niños y adolescentes con síndrome de Tourette o trastorno de tics persistentes. Analizamos los datos para el total de la muestra y por grupos de edad (niños hasta los 10 años y mayores de 10 años).[Resultados] La PUTS obtuvo una buena consistencia interna y correlaciones moderadas entre ítems de la escala (excepto en el ítem uno). Se encontró una buena validez divergente, una adecuada fiabilidad test-retest y una estructura bifactorial (con una dimensión de fenómenos mentales relacionados con el trastorno obsesivo-compulsivo y otra sobre las cualidades y frecuencia de los impulsos premonitorios). Estos resultados se replicaron para ambos grupos de edad, excepto la validez divergente y la fiabilidad test-retest que fueron inferiores en el grupo de menor edad.[Conclusiones] La versión española de la PUTS es una herramienta válida y fiable para evaluar los impulsos premonitorios en población infanto-juvenil, especialmente después de los 10 años.Peer reviewe