The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition

Loyse Hippolyte; Anne M Maillard; Borja Rodriguez-Herreros; Aurélie Pain; Sandra Martin-Brevet; Carina Ferrari; Philippe Conus; Aurélien Macé; Nouchine Hadjikhani; Andres Metspalu; Anu Reigo; Anneli Kolk; Katrin Männik; Mandy Barker; Bertrand Isidor; Cédric Le Caignec; Cyril Mignot; Laurence Schneider; Laurent Mottron; Boris Keren; Albert David; Martine Doco-Fenzy; Marion Gérard; Raphael Bernier; Robin P Goin-Kochel; Ellen Hanson; LeeAnne Green Snyder; 16p11.2 European Consortium, Simons Variation in Individuals Project Consortium; Franck Ramus; Jacques S Beckmann; Bogdan Draganski; Alexandre Reymond; Sébastien Jacquemont

doi:10.1016/j.biopsych.2015.10.021

The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition

Biol Psychiatry. 2016 Jul 15;80(2):129-139. doi: 10.1016/j.biopsych.2015.10.021. Epub 2015 Nov 10.

Authors

Loyse Hippolyte¹, Anne M Maillard¹, Borja Rodriguez-Herreros², Aurélie Pain¹, Sandra Martin-Brevet², Carina Ferrari³, Philippe Conus³, Aurélien Macé⁴, Nouchine Hadjikhani⁵, Andres Metspalu⁶, Anu Reigo⁶, Anneli Kolk⁷, Katrin Männik⁸, Mandy Barker⁹, Bertrand Isidor¹⁰, Cédric Le Caignec¹¹, Cyril Mignot¹², Laurence Schneider¹³, Laurent Mottron¹⁴, Boris Keren¹⁵, Albert David¹⁰, Martine Doco-Fenzy¹⁶, Marion Gérard¹⁷, Raphael Bernier¹⁸, Robin P Goin-Kochel¹⁹, Ellen Hanson²⁰, LeeAnne Green Snyder²¹; 16p11.2 European Consortium, Simons Variation in Individuals Project Consortium; Franck Ramus²², Jacques S Beckmann²³, Bogdan Draganski²⁴, Alexandre Reymond²⁵, Sébastien Jacquemont²⁶

Affiliations

¹ Service de Génétique Médicale, University of Lausanne, Lausanne, Switzerland.
² Service de Génétique Médicale, University of Lausanne, Lausanne, Switzerland; LREN-Département des Neurosciences Cliniques, University of Lausanne, Lausanne, Switzerland.
³ Department of Psychiatry, University of Lausanne, Lausanne, Switzerland.
⁴ Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; SIB Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
⁵ Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
⁶ Department of Genetics, Tartu University Hospital, Tartu, Estonia.
⁷ United Laboratories, and Children's Clinic, Department of Neurology and Neurorehabilitation, Tartu University Hospital, Tartu, Estonia.
⁸ Center for Integrative Genomics, University of Lausanne;Lausanne, Switzerland; Department of Genetics, Tartu University Hospital, Tartu, Estonia.
⁹ CERY Hospital, Department of Child Psychiatry, University of Lausanne, Lausanne, Switzerland.
¹⁰ Service de Génétique Médicale, CHU-Nantes, Nantes.
¹¹ Service de Génétique Médicale, CHU-Nantes, Nantes; Inserm UMR957, Faculté de Médecine, Nantes.
¹² Department of Genetics and Cytogenetics, Unité fonctionnelle de génétique clinique, Groupe Hospitalier Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Centre de Référence "Déficiences intellectuelles de causes rares" and Groupe de Recherche Clinique "Déficience intellectuelle et autisme", UPMC, Paris, France.
¹³ SUPEA, and Service of Neuropsychology and Neurorehabilitation, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
¹⁴ Département de Psychiatrie, Université de Montréal and Hôpital Rivière des Prairies, Montreal, Quebec, Canada.
¹⁵ Department of Genetics and Cytogenetics, Unité fonctionnelle de génétique clinique, Groupe Hospitalier Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁶ Service de Génétique, CHU, Reims.
¹⁷ Department of Genetics and Cytogenetics, Unité fonctionnelle de génétique clinique, Groupe Hospitalier Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Département de Génétique, Hôpital Robert Debré, Université Paris VII-Paris Diderot, Paris, France.
¹⁸ Department of Psychiatry and Behavioral Science, University of Washington, Seattle, Washington.
¹⁹ Department of Pediatrics, Psychology Section, Baylor College of Medicine, Houston, Texas.
²⁰ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
²¹ Clinical Research Associates, New York, New York.
²² Laboratoire de Sciences Cognitives et Psycholinguistique, Département d'Etudes Cognitives, Ecole Normale Supérieure, EHESS, CNRS, PSL Research University, Paris, France.
²³ Service de Génétique Médicale, University of Lausanne, Lausanne, Switzerland; SIB Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
²⁴ LREN-Département des Neurosciences Cliniques, University of Lausanne, Lausanne, Switzerland; Department of Neurology (BD), Max-Planck Institute for Human Cognitive and Brain Science, Leipzig, Germany.
²⁵ Center for Integrative Genomics, University of Lausanne;Lausanne, Switzerland.
²⁶ Service de Génétique Médicale, University of Lausanne, Lausanne, Switzerland. Electronic address: sebastien.jacquemont@umontreal.ca.

PMID: 26742926
DOI: 10.1016/j.biopsych.2015.10.021

Abstract

Background: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported.

Methods: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects.

Results: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs.

Conclusions: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.

Keywords: 16p11.2; ASD; Copy number variation; Inhibition; Language; Memory.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Autistic Disorder* / diagnostic imaging
Autistic Disorder* / genetics
Autistic Disorder* / physiopathology
Child
Child, Preschool
Chromosome Deletion*
Chromosome Disorders* / diagnostic imaging
Chromosome Disorders* / genetics
Chromosome Disorders* / physiopathology
Chromosome Duplication / genetics*
Chromosomes, Human, Pair 16 / genetics*
Cognitive Dysfunction* / diagnostic imaging
Cognitive Dysfunction* / genetics
Cognitive Dysfunction* / physiopathology
DNA Copy Number Variations / genetics*
Executive Function / physiology*
Female
Heterozygote
Humans
Intellectual Disability* / diagnostic imaging
Intellectual Disability* / genetics
Intellectual Disability* / physiopathology
Intelligence / genetics*
Language*
Male
Memory / physiology*
Middle Aged
Motor Skills / physiology*
Pedigree
Young Adult

Supplementary concepts

16p11.2 Deletion Syndrome