Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome
Abstract
Objective:
Method:
Results:
Conclusions:
Method
Samples
Procedure
Statistical Analyses
Exploratory factor analyses.
Latent class analyses.
Replication sample analyses.
Heritability estimates.
Polygenic burden analyses.
Results
Sample Characteristics
Original Sample | Validation Sample | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Characteristic | Probands Only (N=1,191) | Probands and Family Members (N=3,494) | Probands Only (N=527) | Probands and Family Members (N=882) | ||||||||
N | Mean | SD | N | Mean | SD | N | Mean | SD | N | Mean | SD | |
Age (years) | 1,191 | 15.3 | 10.0 | 3,494 | 30.6 | 17.2 | 522 | 21.4 | 15.6 | 864 | 30.0 | 17.5 |
Tourette syndrome | ||||||||||||
Age at onset (years) | 1,131 | 5.8 | 2.5 | 1,692 | 6.1 | 2.7 | 521 | 6.2 | 2.8 | 569 | 6.3 | 2.8 |
Severitya | 1,181 | 11.4 | 2.6 | 3,490 | 4.1 | 4.6 | 478 | 11.7 | 2.5 | 764 | 7.9 | 5.6 |
OCD | ||||||||||||
Age at onset (years) | 442 | 7.1 | 4.0 | 712 | 8.2 | 5.3 | 249 | 7.4 | 3.8 | 299 | 8.0 | 4.4 |
Severitya | 694 | 4.3 | 3.4 | 2,442 | 3.0 | 3.3 | 450 | 5.0 | 3.9 | 681 | 3.9 | 3.8 |
Total N | N | % | Total N | N | % | Total N | N | % | Total N | N | % | |
Male | 1,191 | 944 | 79.3 | 3,494 | 2,140 | 61.2 | 527 | 408 | 77.4 | 882 | 581 | 65.9 |
Parental history of Tourette syndrome or chronic motor or vocal tic disorder | 864 | 385 | 44.6 | — | — | — | — | — | — | — | — | — |
Personal history | ||||||||||||
OCD | 1,135 | 570 | 50.2 | 3,286 | 1,125 | 34.2 | 504 | 219 | 43.5 | 847 | 336 | 39.7 |
ADHD | 1,116 | 628 | 56.3 | 3,220 | 1,013 | 31.5 | 494 | 181 | 36.6 | 830 | 293 | 35.3 |
Mood disorders | 498 | 132 | 26.5 | 1,603 | 487 | 30.4 | — | — | — | — | — | — |
Anxiety disorders | 507 | 176 | 34.7 | 1,620 | 515 | 31.8 | — | — | — | — | — | — |
Disruptive behavior disorders | 390 | 121 | 31.0 | 662 | 192 | 29.0 | — | — | — | — | — | — |
Exploratory Factor Analyses
Factor Loading | |||||
---|---|---|---|---|---|
Category | Item | Factor 1: Tics (Cronbach’s alpha=0.88) | Factor 2: Obsessive-Compulsive Symptoms (Cronbach’s alpha=0.92) | Factor 3: Disinhibition (Cronbach’s alpha=0.77) | Factor 4: Symmetry Symptoms (Cronbach’s alpha=0.87) |
Tourette | Lift chin | 0.67 | 0.02 | –0.09 | –0.06 |
Tourette | Knee-bending | 0.66 | 0.02 | 0.07 | 0.14 |
Tourette | Teeth bearing | 0.63 | 0.10 | 0.07 | –0.17 |
Tourette | Touch chin to shoulder | 0.60 | 0.04 | –0.08 | –0.08 |
Tourette | Tensing buttocks | 0.58 | 0.02 | –0.16 | 0.18 |
Tourette | Deep knee bending | 0.57 | –0.14 | 0.19 | 0.28 |
Tourette | Quick eye turn | 0.56 | 0.13 | –0.07 | –0.04 |
Tourette | Tensing abdomen | 0.56 | –0.03 | –0.15 | 0.12 |
Tourette | Lip pouting | 0.56 | 0.13 | –0.04 | –0.11 |
Tourette | Rolling eyes to one side | 0.55 | 0.02 | –0.10 | –0.01 |
Tourette | Broadening nostrils | 0.55 | 0.20 | –0.22 | –0.08 |
Tourette | Smiling | 0.54 | 0.07 | 0.03 | –0.04 |
Tourette | Opening eyes wide | 0.52 | 0.10 | –0.10 | 0.01 |
Tourette | Flexing or extending ankle | 0.52 | 0.12 | –0.13 | 0.07 |
Tourette | Kicking | 0.52 | –0.01 | 0.32 | 0.03 |
Tourette | Sticking tongue out | 0.51 | 0.06 | 0.24 | –0.13 |
Tourette | Shrugging shoulders | 0.51 | 0.00 | 0.00 | –0.07 |
Tourette | Nose twitching | 0.50 | 0.06 | –0.18 | –0.06 |
Tourette | Squatting | 0.49 | –0.17 | 0.19 | 0.29 |
Tourette | Biting tongue | 0.48 | 0.13 | –0.03 | 0.02 |
Tourette | Touching | 0.48 | –0.14 | 0.22 | 0.35 |
Tourette | Squinting | 0.48 | 0.13 | –0.15 | –0.01 |
Tourette | Tapping | 0.48 | –0.07 | 0.12 | 0.26 |
Tourette | Jerking shoulder | 0.47 | 0.00 | –0.05 | 0.02 |
Tourette | Counting with fingers | 0.46 | 0.02 | 0.03 | 0.20 |
Tourette | Bending or gyrating | 0.45 | –0.03 | 0.31 | 0.07 |
Tourette | Pulling back pencil | 0.43 | –0.02 | 0.13 | 0.17 |
Tourette | Throwing head back | 0.43 | 0.00 | –0.09 | 0.04 |
Tourette | Skipping | 0.42 | –0.08 | 0.28 | 0.05 |
Tourette | Chewing on lip | 0.42 | 0.15 | –0.04 | –0.11 |
Tourette | Unusual postures | 0.42 | –0.03 | 0.28 | 0.09 |
Tourette | Slower movements | 0.41 | –0.02 | 0.20 | 0.41 |
OCD | Needs to touch, tap, or rub things | 0.41 | 0.13 | 0.14 | 0.39 |
Tourette | Eye blinking | 0.41 | 0.15 | –0.27 | –0.04 |
Tourette | Syllables | 0.40 | –0.16 | 0.40 | 0.05 |
OCD | Contamination concern | 0.00 | 0.77 | –0.23 | –0.05 |
OCD | Hoarding obsessions | –0.24 | 0.76 | 0.43 | –0.01 |
OCD | Illness concern | 0.04 | 0.73 | –0.13 | 0.02 |
OCD | Hoarding compulsions | –0.21 | 0.70 | 0.42 | –0.03 |
OCD | Dirt or germ obsessions | –0.04 | 0.70 | –0.16 | 0.08 |
OCD | Fears harming others if not careful | 0.03 | 0.66 | 0.14 | 0.07 |
OCD | Fears responsible for something terrible | 0.03 | 0.65 | 0.05 | 0.19 |
OCD | Thoughts may influence the outcome of some events if does certain things | –0.02 | 0.63 | –0.09 | 0.32 |
OCD | Checks no self-harm | 0.03 | 0.62 | 0.08 | –0.08 |
OCD | Fears harming others | 0.08 | 0.62 | 0.01 | 0.09 |
OCD | Fears losing things | –0.02 | 0.62 | 0.10 | 0.18 |
OCD | Contamination compulsions | 0.08 | 0.61 | –0.12 | 0.04 |
OCD | Contamination obsessions | 0.22 | 0.61 | –0.08 | 0.03 |
OCD | Checks nothing terrible | 0.05 | 0.60 | 0.11 | –0.02 |
OCD | Fears will steal things | 0.06 | 0.60 | 0.22 | –0.16 |
OCD | Religious obsessions | 0.06 | 0.60 | 0.03 | 0.06 |
OCD | Concerned with bodily waste | 0.05 | 0.59 | –0.03 | 0.09 |
OCD | Morality obsessions | 0.03 | 0.58 | –0.08 | 0.20 |
OCD | Compulsions to prevent harm | 0.25 | 0.57 | –0.03 | 0.10 |
OCD | Urges to offend | –0.05 | 0.57 | 0.56 | –0.10 |
OCD | Checks no harm | 0.07 | 0.57 | 0.08 | 0.12 |
OCD | Violent obsessions | 0.02 | 0.56 | 0.13 | 0.08 |
OCD | Fears self-harm | 0.19 | 0.56 | –0.03 | 0.04 |
OCD | Thoughts can influence the outcome of some events if does certain things | –0.02 | 0.54 | –0.10 | 0.33 |
OCD | Mental rituals | –0.04 | 0.53 | 0.00 | 0.34 |
OCD | Fears acting on an unwanted impulse | 0.09 | 0.53 | 0.29 | 0.12 |
OCD | Self-harm urges | 0.11 | 0.52 | 0.35 | 0.01 |
OCD | Superstitious fears | 0.02 | 0.50 | –0.14 | 0.35 |
OCD | Sexual obsessions | 0.13 | 0.49 | 0.18 | 0.14 |
OCD | Need to confess | 0.00 | 0.49 | 0.12 | 0.18 |
OCD | Animal obsessions | –0.08 | 0.48 | 0.00 | 0.12 |
OCD | Need to explore surroundings | –0.14 | 0.46 | 0.42 | 0.03 |
OCD | Concerned with a part of body or appearance | 0.02 | 0.45 | 0.05 | 0.20 |
OCD | Superstitious behaviors | 0.03 | 0.42 | –0.08 | 0.34 |
OCD | Urges to do sudden and reckless things | 0.11 | 0.40 | 0.30 | 0.13 |
Tourette | Coprolalia | 0.25 | 0.05 | 0.71 | 0.00 |
Tourette | Copropraxia | 0.27 | 0.06 | 0.66 | –0.08 |
Tourette | Echolalia | 0.25 | –0.10 | 0.56 | 0.23 |
OCD | Urges to be destructive | 0.02 | 0.51 | 0.55 | –0.02 |
OCD | Urges to injure or mutilate others | –0.10 | 0.52 | 0.55 | –0.17 |
Tourette | Words | 0.31 | 0.04 | 0.54 | 0.05 |
Tourette | Palilalia | 0.27 | –0.02 | 0.50 | 0.25 |
Tourette | Animal or bird noises | 0.26 | 0.06 | 0.41 | –0.11 |
OCD | Symmetry obsessions | –0.07 | 0.09 | –0.04 | 0.82 |
OCD | Needs certain things to be symmetrical | –0.02 | 0.06 | –0.01 | 0.76 |
OCD | Ordering or arranging compulsions | –0.10 | 0.11 | 0.07 | 0.73 |
OCD | Needs to have certain things evened up | 0.08 | 0.06 | –0.05 | 0.73 |
OCD | Thoughts about evening things up | 0.07 | 0.08 | –0.01 | 0.73 |
OCD | Thoughts about lining things up | –0.01 | 0.09 | –0.01 | 0.71 |
OCD | Obsessions about exactness | –0.03 | 0.20 | –0.05 | 0.70 |
OCD | Rereads or rewrites things | 0.06 | 0.20 | 0.05 | 0.59 |
OCD | Needs to repeat routine activities | 0.03 | 0.14 | 0.11 | 0.58 |
OCD | Counting compulsions | 0.11 | 0.14 | 0.05 | 0.54 |
OCD | Has to do things the same way every time | –0.11 | 0.22 | 0.21 | 0.47 |
OCD | Needs to know or remember certain things | 0.08 | 0.36 | 0.05 | 0.44 |
OCD | Checks that did not make mistakes | 0.05 | 0.40 | –0.09 | 0.43 |
Tourette | Writing the same letter or word over and over | 0.20 | 0.04 | 0.03 | 0.42 |
OCD | Checks things | 0.11 | 0.35 | –0.11 | 0.42 |
Latent Class Analyses
Replication Analyses
Heritability Analyses
Type of Analysis | H2r | SE | p |
---|---|---|---|
Latent class analyses | |||
Class 1: Tourette+OCD+ADHD | 0.63 | 0.09 | 2.0×10–13 |
Class 2: Symmetry symptoms | 0.38 | 0.10 | 0.001 |
Class 3: Tourette+ADHD | 0.47 | 0.08 | 3.3×10–29 |
Class 4: Tics only | 0.28 | 0.08 | 0.001 |
Class 5: Unaffected | — | — | — |
Exploratory factor analyses | |||
Factor 1: Tics | 0.25 | 0.04 | 2.6×10–13 |
Factor 2: Obsessive-compulsive symptoms | 0.46 | 0.03 | 8.6×10–41 |
Factor 3: Disinhibition | 0.35 | 0.03 | 4.2×10–34 |
Factor 4: Symmetry symptoms | 0.39 | 0.03 | 7.2×10–31 |
Polygenic Burden
Discussion
Limitations
Acknowledgments
Footnotes
Supplementary Material
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