Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Yu, Dongmei; Sul, Jae Hoon; Tsetsos, Fotis; Nawaz, Muhammad Sulaman; Huang, Alden; Zelaya, Ivette; Illmann, Cornelia; Osiecki, Lisa; Darrow, Sabrina M.; Hirschtritt, Matthew E.; Greenberg, Erica; Müller-Vahl, Kirsten; Stuhrmann, Manfred; Dion, Yves; Rouleau, Guy A.; Aschauer, H.N.; Stamenkovic, M.; Schlögelhofer, Monika; Sandor, Paul; Barr, Cathy L.; Grados, Marco A.; Singer, Harvey S.; Nöthen, Markus M.; Hebebrand, Johannes; Hinney, Anke; King, Robert A.; Fernandez, Thomas; Barta, Csaba; Tárnok, Zsanett; Nagy, Péter; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Budman, Cathy L.; Rizzo, Renata; Lyon, Gholson J.; McMahon, William M.; Batterson, James R.; Cath, Daniëlle C.; Malaty, Irene A.; Okun, Michael S.; Berlin, Cheston M.; Woods, Douglas W.; Lee, Paul C.; Jankovic, Joseph; Robertson, Mary M.; Gilbert, Donald L.; Brown, Lawrence W.; Coffey, Barbara J.; Dietrich, Andrea; Hoekstra, Pieter J.; Kuperman, Samuel; Zinner, Samuel H.; Lúðvígsson, Pétur; Sæmundsen, Evald; Thorarensen, Ólafur; Atzmon, Gil; Barzilai, Nir; Wagner, Michael; Moessner, Rainald; Ophoff, Roel A.; Pato, Carlos N.; Pato, Michele T.; Knowles, James A.; Roffman, Joshua L.; Smoller, Jordan W.; Buckner, Randy L.; Willsey, A. Jeremy; Tischfield, Jay A.; Heiman, Gary A.; Stefánsson, Hreinn; Stefánsson, Kāri; Posthuma, Daniëlle; Cox, Nancy J.; Pauls, David L.; Freimer, Nelson B.; Neale, Benjamin M.; Davis, Lea K.; Paschou, Peristera; Coppola, Giovanni; Mathews, Carol A.; Scharf, Jeremiah M.

doi:10.1176/appi.ajp.2018.18070857

Cited by 249 publications

(187 citation statements)

References 30 publications

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“…In total, 4,232 cases and 8,283 ancestry-matched controls were used for the analysis, which resulted in 8,868,895 variants overlapping in the meta-analysis. These summary statistics correspond to the GWAS carried out by Yu et al (17), without samples from the Tic Genetic Consortium.…”

Section: Data Sourcesmentioning

confidence: 69%

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Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Yang¹,

Wu²,

Lee

et al. 2019

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Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Obsessive-Compulsive Disorder (OCD), and Tourette Syndrome (TS) are among the most prevalent neurodevelopmental psychiatric disorders of childhood and adolescence. High comorbidity rates across these four disorders point toward a common etiological thread that could be connecting them across the repetitive behaviors-impulsivity-compulsivity continuum. Aiming to uncover the shared genetic basis across ADHD, ASD, OCD, and TS, we undertake a systematic cross-disorder meta-analysis, integrating summary statistics from all currently available genome-wide association studies (GWAS) for these disorders, as made available by the Psychiatric Genomics Consortium (PGC) and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). We present analysis of a combined dataset of 93,294 individuals, across 6,788,510 markers and investigate associations on the single-nucleotide polymorphism (SNP), gene and pathway levels across all four disorders but also pairwise. In the ADHD-ASD-OCD-TS cross disorder GWAS meta-analysis, we uncover in total 297 genomewide significant variants from six LD (linkage disequilibrium) -independent genomic risk regions. Out of these genomewide significant association results, 199 SNPs, that map onto four genomic regions, show high posterior probability for association with at least three of the studied disorders (m-value>0.9). Gene-based GWAS metaanalysis across ADHD, ASD, OCD, and TS identified 21 genes significantly associated under Bonferroni correction. Out of those, 15 could not be identified as significantly associated based on the individual disorder GWAS dataset, indicating increased power in the cross-disorder comparisons. Cross-disorder tissue-specificity analysis implicates the Hypothalamus-Pituitary-Adrenal axis (stress response) as possibly underlying shared pathophysiology across ADHD, ASD, OCD, and TS. Our work highlights genetic variants and genes that may contribute to overlapping neurobiology across the four studied disorders and highlights the value of re-defining the framework for the study across this spectrum of highly comorbid disorders, by using transdiagnostic approaches.

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Section: Data Sourcesmentioning

confidence: 69%

“…Over the past few years, twelve genome-wide significant loci have been identified for ADHD (13), and five genome-wide significant loci were described for ASD (14,15). For OCD no genome-wide significant loci have been detected to date (16), while one genome-wide significant locus was recently reported for TS (17).…”

Section: Introductionmentioning

confidence: 99%

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Yang¹,

Wu²,

Lee

et al. 2019

Preprint

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“…Genomic evidence reinforces this trans-diagnostic paradigm, facilitated by the GWAS now available for a number of psychiatric disorders in addition to schizophrenia (8-14). Linkage disequilibrium (LD) score regression has demonstrated that schizophrenia displays positive genomic correlation with several psychiatric phenotypes (15), with the most statistically significant relationship observed with bipolar disorder (BIP).…”

Section: Introductionmentioning

confidence: 85%

“…The largest European ancestry GWAS with full genome-wide summary statistics available was obtained for schizophrenia (N = 105318, Pardiñas et al (1)) and seven other psychiatric disorders. The other disorders and their respective GWAS were as follows: bipolar disorder (BIP, N = 51710) (8), attention-deficit/hyperactivity disorder (ADHD, N = 53293 [European subset]) (9), major depressive disorder (MDD, N=173005) [excluding the 23andMe cohorts for which full summary statistics are not publicly available]) (10), obsessive compulsive disorder (OCD, N = 9725) (11), eating disorder (ED, N=14477) (12), autism spectrum disorder (ASD, N=46351) (13), and Tourette’s Syndrome (TS, N=14307) (14). Schizophrenia summary statistics were downloaded from the Walters group data repository (https://walters.psycm.cf.ac.uk/), whilst the other seven summary statistics were obtained from the website of the psychiatric genomics consortium (PGC, https://www.med.unc.edu/pgc/results-and-downloads/).…”

Section: Methodsmentioning

confidence: 99%

Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations

Cairns

2019

Preprint

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ABSTRACTThe complex aetiology of schizophrenia is postulated to share factors with other psychiatric disorders. Recently, this has been supported by genome-wide association studies, with several psychiatric phenotypes displaying high genomic correlation with schizophrenia. We sought to investigate pleiotropy amongst the common variant genomics of schizophrenia and seven other psychiatric disorders using a multimarker test of association. Gene-based analysis of common variation revealed over 50 schizophrenia-associated genes shared with other psychiatric phenotypes; including bipolar disorder, major depressive disorder, ADHD, and autism spectrum disorder. In addition, we uncovered 78 genes significantly enriched with common variant associations for schizophrenia that were not linked to any of these seven disorders (P > 0.05). Transcriptomic imputation was then leveraged to investigate the functional significance of variation mapped to these genes, prioritising several interesting functional candidates. Pairwise meta-analysis of schizophrenia and each psychiatric phenotype further revealed 330 significantly associated genes (PMeta < 2.7 × 10−6) that were only nominally associated with each disorder individually (P < 0.05). Multivariable gene-set association suggested that common variation enrichment within biologically constrained genes observed for schizophrenia also occurs across several psychiatric phenotypes. These analyses consolidate the overlap between the genomic architecture of schizophrenia and other psychiatric disorders and uncovered several pleiotropic genes which warrant further investigation.AUTHOR SUMMARYSchizophrenia and other psychiatric disorders have many similarities, and this includes features of their overall genetic risk. Here, we investigate genes which may play a role in schizophrenia as well one or more of seven other psychiatric phenotypes and demonstrate that a number of them are pleiotropic and influence at least one other disorder. We also identify genes amongst the psychiatric disorders studied here which only show association with schizophrenia. Furthermore, we find a number of genes which were only significant when combining genetic association data from schizophrenia and one of the other seven disorders, suggesting there are shared genetic influences that are revealed through the power of joint analysis. This study identifies interesting novel shared (pleiotropic) genes in psychiatry which warrant future study.

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“…We next focused on a subset of phenotypes for which diagnostic heterogeneity 374 information exists (ADHD, 43 anorexia nervosa, 44 autism spectrum disorder, 45 bipolar disorder, 46 375 major depressive disorder, 47 schizophrenia, 48 anxiety, 49 and Tourette syndrome; 38 Figure 4 and 376 Table S1). With these phenotypes we tested whether diagnostic information such as number of 377 diagnostic combinations and total symptoms contribute to risk locus effect size distribution 378 descriptive statistics.…”

Section: Correlates Of Effect Size Distribution 303mentioning

confidence: 99%

Natural selection influenced the genetic architecture of brain structure, behavioral and neuropsychiatric traits

Wendt

Pathak

Overstreet³

et al. 2020

Preprint

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Natural selection has shaped the phenotypic characteristics of human populations.Genome-wide association studies (GWAS) have elucidated contributions of thousands of common variants with small effects on an individual's predisposition to complex traits (polygenicity), as well as wide-spread sharing of risk alleles across traits in the human phenome (pleiotropy). It remains unclear how the pervasive effects of natural selection influence polygenicity in brain-related traits. We investigate these effects by annotating the genome with measures of background (BGS) and positive selection, indications of Neanderthal introgression, measures of functional significance including loss-of-function (LoF) intolerant and genic regions, and genotype networks in 75 brain-related traits. Evidence of natural selection was determined using binary annotations of top 2%, 1%, and 0.5% of selection scores genome-wide.We detected enrichment (q<0.05) of SNP-heritability at loci with elevated BGS (7 phenotypes) and in genic (34 phenotypes) and LoF-intolerant regions (67 phenotypes). BGS (top 2%) significantly predicted effect size variance for trait-associated loci (σ 2 parameter) in 75 brainrelated traits (β=4.39x10 -5 , p=1.43x10 -5 , model r 2 =0.548). By including the number of DSM-5 diagnostic combinations per psychiatric disorder, we substantially improved model fit (σ 2 ~ BTop2% × Genic × diagnostic combinations; model r 2 =0.661). We show that GWAS with larger variance in risk locus effect sizes are collectively predicted by the effects of loci under strong BGS and in regulatory regions of the genome. We further show that diagnostic complexity exacerbates this relationship and perhaps dampens the ability to detect psychiatric risk loci.

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Interrogating the Genetic Determinants of Tourette’s Syndrome and Other Tic Disorders Through Genome-Wide Association Studies

Cited by 249 publications

References 30 publications

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations

Natural selection influenced the genetic architecture of brain structure, behavioral and neuropsychiatric traits

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