Table 1.
List of genes that have so far been implicated in TS etiology.
| Experimental approach by which the gene was initially identified | Gene | Protein function | Study sample size | References |
|---|---|---|---|---|
| CANDIDATE GENE | ||||
| Dopamine receptor D2 | DRD2 | Dopamine receptor | 147 TS cases/314 controls | Comings et al., 1991 |
| 225 TS cases/67 controls | Comings et al., 1996 | |||
| 151 TS cases/183 controls | Lee et al., 2005 | |||
| 69 trios | Herzberg et al., 2010 | |||
| Dopamine receptor D4 | DRD4 | Dopamine receptor | 12 trios/3 large families | Grice et al., 1996 |
| 61 OCD cases with and without tics | Cruz et al., 1997 | |||
| 110 trios | Díaz-Anzaldúa et al., 2004 | |||
| Dopamine transporter [Solute carrier family 6 (neurotransmitter transporter), member 3] | DAT1 (SLC6A3) | Dopamine transporter | 225 TS cases/67 controls | Comings et al., 1996 |
| 103 trios | Tarnok et al., 2007 | |||
| 266 TS cases/236 controls | Yoon et al., 2007 | |||
| 110 trios | Díaz-Anzaldúa et al., 2004 | |||
| Dopamine beta hydroxylase | DBH | Dopamine metabolism (transformation of dopamine to norepinephrine) | 352 TS cases/148 controls | Comings et al., 1996 |
| Monoamine oxidase-A | MAOA | Dopamine and serotonin metabolism (inactivation) | 229 TS cases/90 relatives of TS/57 controls | Gade et al., 1998 |
| 110 trios | Díaz-Anzaldúa et al., 2004 | |||
| Serotonin receptor 1A | HTR1A | Serotonin receptor | 56 TS cases/20 controls | Lam et al., 1996 |
| Serotonin receptor 2C | HTR2C | Serotonin receptor | 87 TS cases/311 controls | Dehning et al., 2010 |
| Serotonin transporter [Solute carrier family 6 (neurotransmitter transporter), member 4] | SERT (SLC6A4) | Serotonin transporter | 151 TS cases/858 controls | Moya et al., 2013 |
| 5-HTTLPR locus | – | 151 TS cases/858 controls | Moya et al., 2013 | |
| Tryptophan hydroxylase | TPH2 | Serotonin metabolism (synthesis) | 98 TS cases/178 controls | Mössner et al., 2007 |
| Glutamate transporter [Solute carrier family 1 (glial high affinity glutamate transporter), member 3] | EAAT1 (SLC1A3) | Glutamate transporter | 256 TS cases/224 controls | Adamczyk et al., 2011 |
| CHROMOSOMAL ABERRATIONS | ||||
| Slit and Trk-like, Family Member 1 | SLITRK1 | Neurite outgrowth | 175 TS cases/2148 controls | Abelson et al., 2005 |
| 222 trios | Karagiannidis et al., 2012 | |||
| Inner mitochondrial membrane protein 2L | IMMP2L | Targets proteins to the inner mitochondrial membrane (exact role unknown) | De novo duplication in one TS patient | Petek et al., 2001 |
| De novo duplication in one TS patient | Kroisel et al., 2001 | |||
| De novo translocation in one TS patient | Patel et al., 2011 | |||
| Contactin associated protein-like 2 | CNTNAP2 | Cell-cell interaction (myelinated axon-glia junction) and membrane potential (interaction with voltage-activated potassium channel) | One family | Verkerk et al., 2003 |
| 460 TS cases/1131 controls | Fernandez et al., 2012 | |||
| Neuroligin 4 | NLGN4 | Post-synaptic cell adhesion (synaptogenesis and synapse remodeling) | One family | Lawson-Yuen et al., 2008 |
| COPY NUMBER VARIANTS | ||||
| Neurexin 1 | NRXN1 | Pre-synaptic cell adhesion (synapse formation) | 111 TS cases/73 controls | Sundaram et al., 2010 |
| 460 TS cases/1131 controls | Fernandez et al., 2012 | |||
| 210 TS cases/285 controls | Nag et al., 2013 | |||
| Arylacetamide deacetylase | AADAC | Detoxification (drug metabolism)—Unknown function in the brain | 111 TS cases/73 controls | Sundaram et al., 2010; |
| 243 TS cases/1571 controls (initial study) | Bertelsen et al., 2015 | |||
| 1181 TS cases/118730 controls (meta-analysis) | ||||
| Catenin alpha 3 | CTNNA3 | Cytoskeleton modeling (actin fillament assembly) | 111 TS cases/73 controls | Sundaram et al., 2010 |
| 460 TS cases/1131 controls | Fernandez et al., 2012 | |||
| Fibrous sheath CABYR binding protein | FSCB | Ca2+-binding protein involved in fibrous sheath biogenesis | 111 TS cases/73 controls | Sundaram et al., 2010 |
| Voltage-gated potassium channel (KCNE1, KCNE2) and regulator of calcineurin 1 (RCAN1) | KCNE1-KCNE2-RCAN1 locus | Neuronal cell membrane repolarization (KCNE1, KCNE2) and intracellular calcineurin-mediated signaling (RCAN1) | 111 TS cases/73 controls | Sundaram et al., 2010 |
| Collagen, type VIII, alpha 1 | COL8A1 | Connective tissue and basement membrane component (extracellular matrix collagen) | 210 TS cases/285 controls | Nag et al., 2013 |
| LINKAGE STUDIES | ||||
| Histidine decarboxylase | HDC | Histidine metabolism (synthesis) | One large family | Ercan-Sencicek et al., 2010 |
| 520 trios | Karagiannidis et al., 2013 | |||
| GENOMEWIDE ASSOCIATION STUDIES | ||||
| Collagen, type XXVII, alpha 1 | COL27A1 * | Connective tissue component (extracellular matrix collagen) | 1285 TS cases/4964 controls (initial GWAS) | Scharf et al., 2013 |
| 1496 TS cases/5249 controls (meta-analysis) | ||||
| Netrin 4 | rs2060546 (proximal to NTN4) | Extracellular protein that directs axon outgrowth and guidance | 609 TS cases/610 controls (initial analysis) | Paschou et al., 2014 |
| 1894 TS cases/5574 controls (meta-analysis) | ||||
As described in detail in the text, associations still remain inconclusive with difficulties in replicating original positive findings. To date, the heterogeneity of the disorder and small sample sizes have been hampering the identification of TS susceptibility genes and, large scale studies like the ones described in this perspective, hold the promise to unravel the genetic basis of TS.
*
Only the top hit is shown here. No SNP reached genomewide significance levels.