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Abstract Breaking atmospheric gravity waves (GWs) in the tropical stratosphere are essential in driving the roughly 2‐year oscillation of zonal winds in this region known as the Quasi‐Biennial Oscillation (QBO). As Global Climate Models (GCM)s are not typically able to directly resolve the spectrum of waves required to drive the QBO, parameterizations are necessary. Such parameterizations often require knowledge of poorly constrained physical parameters. In the case of the spectral gravity parameterization used in this work, these parameters are the total equatorial GW stress and the half width of phase speed distribution. Radiosonde observations are used to obtain the period and amplitude of the QBO, which are compared against values obtained from a GCM. We utilize two established calibration techniques to obtain estimates of the range of plausible parameter values: History matching & Ensemble Kalman Inversion (EKI). History matching is found to reduce the size of the initial range of plausible parameters by a factor of 98%, requiring only 60 model integrations. EKI cannot natively provide any uncertainty quantification but is able to produce a single best estimate of the calibrated values in 25 integrations. When directly comparing the approaches using the Calibrate, Emulate, Sample method to produce a posterior estimate from EKI, history matching produces more compact posteriors with fewer model integrations at lower ensemble sizes compared to EKI; however, these differences become less apparent at higher ensemble sizes. 

Abstract Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3 , raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS. 

Abstract Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.