TY - JOUR
T1 - Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities
AU - Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study
AU - 16p11.2 European Consortium
AU - Simons Variation in Individuals Project (VIP) Consortium
AU - D'Angelo, Debra
AU - Lebon, Sébastien
AU - Chen, Qixuan
AU - Martin-Brevet, Sandra
AU - Snyder, Lee Anne Green
AU - Hippolyte, Loyse
AU - Hanson, Ellen
AU - Maillard, Anne M.
AU - Faucett, W. Andrew
AU - Macé, Aurélien
AU - Pain, Aurélie
AU - Bernier, Raphael
AU - Chawner, Samuel J.R.A.
AU - David, Albert
AU - Andrieux, Joris
AU - Aylward, Elizabeth
AU - Baujat, Genevieve
AU - Caldeira, Ines
AU - Conus, Philippe
AU - Ferrari, Carrina
AU - Forzano, Francesca
AU - Gérard, Marion
AU - Goin-Kochel, Robin P.
AU - Grant, Ellen
AU - Hunter, Jill V.
AU - Isidor, Bertrand
AU - Jacquette, Aurélia
AU - Jønch, Aia E.
AU - Keren, Boris
AU - Lacombe, Didier
AU - Le Caignec, Cédric
AU - Martin, Christa Lese
AU - Männik, Katrin
AU - Metspalu, Andres
AU - Mignot, Cyril
AU - Mukherjee, Pratik
AU - Owen, Michael J.
AU - Passeggeri, Marzia
AU - Rooryck-Thambo, Caroline
AU - Rosenfeld, Jill A.
AU - Spence, Sarah J.
AU - Steinman, Kyle J.
AU - Tjernagel, Jennifer
AU - Van Haelst, Mieke
AU - Shen, Yiping
AU - Draganski, Bogdan
AU - Sherr, Elliott H.
AU - Ledbetter, David H.
AU - van den Bree, Marianne B.M.
AU - Aaronson, Benjamin
N1 - Publisher Copyright:
© 2016 American Medical Association. All rights reserved.
PY - 2016/1
Y1 - 2016/1
N2 - IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0%in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0%and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
AB - IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0%in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0%and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
UR - http://www.scopus.com/inward/record.url?scp=84954141702&partnerID=8YFLogxK
U2 - 10.1001/jamapsychiatry.2015.2123
DO - 10.1001/jamapsychiatry.2015.2123
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C2 - 26629640
AN - SCOPUS:84954141702
SN - 2168-622X
VL - 73
SP - 20
EP - 30
JO - JAMA Psychiatry
JF - JAMA Psychiatry
IS - 1
ER -