TY - JOUR
T1 - Identification of two heritable cross-disorder endophenotypes for tourette syndrome
AU - Tourette Syndrome Association International Consortium for Genetics
AU - Darrow, Sabrina M.
AU - Hirschtritt, Matthew E.
AU - Davis, Lea K.
AU - Illmann, Cornelia
AU - Osiecki, Lisa
AU - Grados, Marco
AU - Sandor, Paul
AU - Dion, Yves
AU - King, Robert
AU - Pauls, David
AU - Budman, Cathy L.
AU - Cath, Danielle C.
AU - Greenberg, Erica
AU - Lyon, Gholson J.
AU - Yu, Dongmei
AU - McGrath, Lauren M.
AU - McMahon, William M.
AU - Lee, Paul C.
AU - Delucchi, Kevin L.
AU - Scharf, Jeremiah M.
AU - Mathews, Carol A.
N1 - Funding Information:
Supported by grants R01 MH096767 (principal investigator: Carol Mathews), K23 MH085057 (principal investigator: Jeremiah Scharf), and K02MH00508 (principal investigator: David Pauls) fromNIMH; grants U01 NS040024 (principal investigators: David Pauls/Jeremiah Scharf) and R01 NS016648 (principal investigator: David Pauls) from the National Institute of Neurological Disorders and Stroke (NINDS); and a grant from the Tourette Association of America.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Objective: Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. Method: Assessments for Tourette syndrome,OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome,OCD, and ADHD were estimated. Results: The authors identified two cross-disorder symptombased phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/ be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived froman OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not. Conclusions: The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.
AB - Objective: Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. Method: Assessments for Tourette syndrome,OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome,OCD, and ADHD were estimated. Results: The authors identified two cross-disorder symptombased phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/ be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived froman OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not. Conclusions: The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.
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U2 - 10.1176/appi.ajp.2016.16020240
DO - 10.1176/appi.ajp.2016.16020240
M3 - Article
C2 - 27809572
AN - SCOPUS:85017013549
SN - 0002-953X
VL - 174
SP - 387
EP - 396
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 4
ER -