Investigation of gene-environment interactions in relation to tic severity
Abdulkadir, Mohamed; Yu, Dongmei; Osiecki, Lisa; King, Robert A; Fernandez, Thomas V; Brown, Lawrence W; Cheon, Keun-Ah; Coffey, Barbara J; Garcia-Delgar, Blanca; Gilbert, Donald L; Grice, Dorothy E; Hagstrøm, Julie; Hedderly, Tammy; Heyman, Isobel; Hong, Hyun Ju; Huyser, Chaim; Ibanez-Gomez, Laura; Kim, Young Key; Kim, Young-Shin; Koh, Yun-Joo; Kook, Sodahm; Kuperman, Samuel; Leventhal, Bennett; Madruga-Garrido, Marcos; Maras, Athanasios; Mir, Pablo; Morer, Astrid; Münchau, Alexander; Plessen, Kerstin J; Roessner, Veit; Shin, Eun-Young; Song, Dong-Ho; Song, Jungeun; Visscher, Frank; Zinner, Samuel H; Mathews, Carol A; Scharf, Jeremiah M; Tischfield, Jay A; Heiman, Gary A; Dietrich, Andrea; Hoekstra, Pieter J
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.
PMCID:8536549
PMID: 34389898
ISSN: 1435-1463
CID: 5038862
Synaptic processes and immune-related pathways implicated in Tourette syndrome
Tsetsos, Fotis; Yu, Dongmei; Sul, Jae Hoon; Huang, Alden Y; Illmann, Cornelia; Osiecki, Lisa; Darrow, Sabrina M; Hirschtritt, Matthew E; Greenberg, Erica; Muller-Vahl, Kirsten R; Stuhrmann, Manfred; Dion, Yves; Rouleau, Guy A; Aschauer, Harald; Stamenkovic, Mara; 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 V; Barta, Csaba; Tarnok, Zsanett; Nagy, Peter; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Budman, Cathy L; Rizzo, Renata; Lyon, Gholson J; McMahon, William M; Batterson, James R; Cath, Danielle C; Malaty, Irene A; Okun, Michael S; Berlin, Cheston; 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; Wagner, Michael; Knowles, James A; Jeremy Willsey, A; Tischfield, Jay A; Heiman, Gary A; Cox, Nancy J; Freimer, Nelson B; Neale, Benjamin M; Davis, Lea K; Coppola, Giovanni; Mathews, Carol A; Scharf, Jeremiah M; Paschou, Peristera; Barr, Cathy L; Batterson, James R; Berlin, Cheston; Budman, Cathy L; Cath, Danielle C; Coppola, Giovanni; Cox, Nancy J; Darrow, Sabrina; Davis, Lea K; Dion, Yves; Freimer, Nelson B; Grados, Marco A; Greenberg, Erica; Hirschtritt, Matthew E; Huang, Alden Y; Illmann, Cornelia; King, Robert A; Kurlan, Roger; Leckman, James F; Lyon, Gholson J; Malaty, Irene A; Mathews, Carol A; McMahon, William M; Neale, Benjamin M; Okun, Michael S; Osiecki, Lisa; Robertson, Mary M; Rouleau, Guy A; Sandor, Paul; Scharf, Jeremiah M; Singer, Harvey S; Smit, Jan H; Sul, Jae Hoon; Yu, Dongmei; Aschauer, Harald Aschauer Harald; Barta, Csaba; Budman, Cathy L; Cath, Danielle C; Depienne, Christel; Hartmann, Andreas; Hebebrand, Johannes; Konstantinidis, Anastasios; Mathews, Carol A; Müller-Vahl, Kirsten; Nagy, Peter; Nöthen, Markus M; Paschou, Peristera; Rizzo, Renata; Rouleau, Guy A; Sandor, Paul; Scharf, Jeremiah M; Schlögelhofer, Monika; Stamenkovic, Mara; Stuhrmann, Manfred; Tsetsos, Fotis; Tarnok, Zsanett; Wolanczyk, Tomasz; Worbe, Yulia; Brown, Lawrence; Cheon, Keun-Ah; Coffey, Barbara J; Dietrich, Andrea; Fernandez, Thomas V; Garcia-Delgar, Blanca; Gilbert, Donald; Grice, Dorothy E; Hagstrøm, Julie; Hedderly, Tammy; Heiman, Gary A; Heyman, Isobel; Hoekstra, Pieter J; Huyser, Chaim; Kim, Young Key; Kim, Young-Shin; King, Robert A; Koh, Yun-Joo; Kook, Sodahm; Kuperman, Samuel; Leventhal, Bennett L; Madruga-Garrido, Marcos; Mir, Pablo; Morer, Astrid; Münchau, Alexander; Plessen, Kerstin J; Roessner, Veit; Shin, Eun-Young; Song, Dong-Ho; Song, Jungeun; Tischfield, Jay A; Willsey, A Jeremy; Zinner, Samuel; Aschauer, Harald; Barr, Cathy L; Barta, Csaba; Batterson, James R; Berlin, Cheston; Brown, Lawrence; Budman, Cathy L; Cath, Danielle C; Coffey, Barbara J; Coppola, Giovanni; Cox, Nancy J; Darrow, Sabrina; Davis, Lea K; Depienne, Christel; Dietrich, Andrea; Dion, Yves; Fernandez, Thomas; Freimer, Nelson B; Gilbert, Donald; Grados, Marco A; Greenberg, Erica; Hartmann, Andreas; Hebebrand, Johannes; Heiman, Gary; Hirschtritt, Matthew E; Hoekstra, Pieter; Huang, Alden Y; Illmann, Cornelia; Jankovic, Joseph; King, Robert A; Kuperman, Samuel; Lee, Paul C; Lyon, Gholson J; Malaty, Irene A; Mathews, Carol A; McMahon, William M; Müller-Vahl, Kirsten; Nagy, Peter; Neale, Benjamin M; Nöthen, Markus M; Okun, Michael S; Osiecki, Lisa; Paschou, Peristera; Rizzo, Renata; Robertson, Mary M; Rouleau, Guy A; Sandor, Paul; Scharf, Jeremiah M; Schlögelhofer, Monika; Singer, Harvey S; Stamenkovic, Mara; Stuhrmann, Manfred; Sul, Jae Hoon; Tarnok, Zsanett; Tischfield, Jay; Tsetsos, Fotis; Willsey, A Jeremy; Woods, Douglas; Worbe, Yulia; Yu, Dongmei; Zinner, Samuel
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.
PMID: 33462189
ISSN: 2158-3188
CID: 4760342