Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Debra D'Angelo; Sébastien Lebon; Qixuan Chen; Sandra Martin-Brevet; LeeAnne Green Snyder; Loyse Hippolyte; Ellen Hanson; Anne M Maillard; W Andrew Faucett; Aurélien Macé; Aurélie Pain; Raphael Bernier; Samuel J R A Chawner; Albert David; Joris Andrieux; Elizabeth Aylward; Genevieve Baujat; Ines Caldeira; Philippe Conus; Carrina Ferrari; Francesca Forzano; Marion Gérard; Robin P Goin-Kochel; Ellen Grant; Jill V Hunter; Bertrand Isidor; Aurélia Jacquette; Aia E Jønch; Boris Keren; Didier Lacombe; Cédric Le Caignec; Christa Lese Martin; Katrin Männik; Andres Metspalu; Cyril Mignot; Pratik Mukherjee; Michael J Owen; Marzia Passeggeri; Caroline Rooryck-Thambo; Jill A Rosenfeld; Sarah J Spence; Kyle J Steinman; Jennifer Tjernagel; Mieke Van Haelst; Yiping Shen; Bogdan Draganski; Elliott H Sherr; David H Ledbetter; Marianne B M van den Bree

doi:10.1001/jamapsychiatry.2015.2123

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Debra D'Angelo, Sébastien Lebon, Qixuan Chen, Sandra Martin-Brevet, LeeAnne Green Snyder, Loyse Hippolyte, Ellen Hanson, Anne M Maillard, W Andrew Faucett, Aurélien Macé, Aurélie Pain, Raphael Bernier, Samuel J R A Chawner, Albert David, Joris Andrieux, Elizabeth Aylward, Genevieve Baujat, Ines Caldeira, Philippe Conus, Carrina FerrariFrancesca Forzano, Marion Gérard, Robin P Goin-Kochel, Ellen Grant, Jill V Hunter, Bertrand Isidor, Aurélia Jacquette, Aia E Jønch, Boris Keren, Didier Lacombe, Cédric Le Caignec, Christa Lese Martin, Katrin Männik, Andres Metspalu, Cyril Mignot, Pratik Mukherjee, Michael J Owen, Marzia Passeggeri, Caroline Rooryck-Thambo, Jill A Rosenfeld, Sarah J Spence, Kyle J Steinman, Jennifer Tjernagel, Mieke Van Haelst, Yiping Shen, Bogdan Draganski, Elliott H Sherr, David H Ledbetter, Marianne B M van den Bree,

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	20-30
Number of pages	11
Journal	JAMA Psychiatry
Volume	73
Issue number	1
DOIs	https://doi.org/10.1001/jamapsychiatry.2015.2123
Publication status	Published - 1 Jan 2016

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10.1001/jamapsychiatry.2015.2123

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D'Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L. G., Hippolyte, L., Hanson, E., Maillard, A. M., Faucett, W. A., Macé, A., Pain, A., Bernier, R., Chawner, S. J. R. A., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P. (2016). Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. JAMA Psychiatry, 73(1), 20-30. https://doi.org/10.1001/jamapsychiatry.2015.2123

@article{87208c987e114e07bc80706aaa935d25,

title = "Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities",

abstract = "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.",

author = "Debra D'Angelo and S{\'e}bastien Lebon and Qixuan Chen and Sandra Martin-Brevet and Snyder, {LeeAnne Green} and Loyse Hippolyte and Ellen Hanson and Maillard, {Anne M} and Faucett, {W Andrew} and Aur{\'e}lien Mac{\'e} and Aur{\'e}lie Pain and Raphael Bernier and Chawner, {Samuel J R A} and Albert David and Joris Andrieux and Elizabeth Aylward and Genevieve Baujat and Ines Caldeira and Philippe Conus and Carrina Ferrari and Francesca Forzano and Marion G{\'e}rard and Goin-Kochel, {Robin P} and Ellen Grant and Hunter, {Jill V} and Bertrand Isidor and Aur{\'e}lia Jacquette and J{\o}nch, {Aia E} and Boris Keren and Didier Lacombe and {Le Caignec}, C{\'e}dric and Martin, {Christa Lese} and Katrin M{\"a}nnik and Andres Metspalu and Cyril Mignot and Pratik Mukherjee and Owen, {Michael J} and Marzia Passeggeri and Caroline Rooryck-Thambo and Rosenfeld, {Jill A} and Spence, {Sarah J} and Steinman, {Kyle J} and Jennifer Tjernagel and {Van Haelst}, Mieke and Yiping Shen and Bogdan Draganski and Sherr, {Elliott H} and Ledbetter, {David H} and {van den Bree}, {Marianne B M} and {van Binsbergen}, E",

year = "2016",

month = jan,

day = "1",

doi = "10.1001/jamapsychiatry.2015.2123",

language = "English",

volume = "73",

pages = "20--30",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "1",

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D'Angelo, D, Lebon, S, Chen, Q, Martin-Brevet, S, Snyder, LG, Hippolyte, L, Hanson, E, Maillard, AM, Faucett, WA, Macé, A, Pain, A, Bernier, R, Chawner, SJRA, David, A, Andrieux, J, Aylward, E, Baujat, G, Caldeira, I, Conus, P, Ferrari, C, Forzano, F, Gérard, M, Goin-Kochel, RP, Grant, E, Hunter, JV, Isidor, B, Jacquette, A, Jønch, AE, Keren, B, Lacombe, D, Le Caignec, C, Martin, CL, Männik, K, Metspalu, A, Mignot, C, Mukherjee, P, Owen, MJ, Passeggeri, M, Rooryck-Thambo, C, Rosenfeld, JA, Spence, SJ, Steinman, KJ, Tjernagel, J, Van Haelst, M, Shen, Y, Draganski, B, Sherr, EH, Ledbetter, DH, van den Bree, MBM 2016, 'Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities', JAMA Psychiatry, vol. 73, no. 1, pp. 20-30. https://doi.org/10.1001/jamapsychiatry.2015.2123

TY - JOUR

T1 - Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

AU - D'Angelo, Debra

AU - Lebon, Sébastien

AU - Chen, Qixuan

AU - Martin-Brevet, Sandra

AU - Snyder, LeeAnne 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 - van Binsbergen, E

PY - 2016/1/1

Y1 - 2016/1/1

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.

U2 - 10.1001/jamapsychiatry.2015.2123

DO - 10.1001/jamapsychiatry.2015.2123

M3 - Article

C2 - 26629640

SN - 2168-622X

VL - 73

SP - 20

EP - 30

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 1

ER -

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

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