Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Loviglio, M N ; Leleu, M ; Männik, K ; Passeggeri, M ; Giannuzzi, G ; Van Der Werf, I ; Waszak, S M ; Zazhytska, M ; Roberts-Caldeira, I ; Gheldof, N ; Migliavacca, E ; Alfaiz, A A ; Hippolyte, L ; Maillard, A M ; Loviglio, Maria Nicla ; Männik, Katrin ; Van Der Werf, Ilse ; Giannuzzi, Giuliana ; Zazhytska, Marianna ; Gheldof, Nele ; Migliavacca, Eugenia ; Alfaiz, Ali A ; Roberts-Caldeira, Inês ; Hippolyte, Loyse ; Maillard, Anne M ; Ferrarini, Alessandra ; Butschi, Florence Niel ; Conrad, Bernard ; Addor, Marie-Claude ; Belfiore, Marco ; Roetzer, Katharina ; Dijck, Anke Van ; Blaumeiser, Bettina ; Kooy, Frank ; Roelens, Filip ; Dheedene, Annelies ; Chiaie, Barbara Delle ; Menten, Björn ; Oostra, Ann ; Caberg, Jean-Hubert ; Carter, Melissa ; Kellam, Barbara ; Stavropoulos, Dimitri J ; Marshall, Christian ; Scherer, Stephen W ; Weksberg, Rosanna ; Cytrynbaum, Cheryl ; Bassett, Anne ; Lowther, Chelsea ; Gillis, Jane ; Mackay, Sara ; Bache, Iben ; Ousager, Lilian B ; Smerdel, Maja Patricia ; Graakjaer, Jesper ; Kjaergaard, Susanne ; Metspalu, Andres ; Mathieu, Michele ; Bonneau, Dominique ; Guichet, Agnes ; Parent, Philippe ; Férec, Claude ; Gerard, Marion ; Plessis, Ghislaine ; Lespinasse, James ; Masurel, Alice ; Marle, Nathalie ; Faivre, Laurence ; Callier, Patrick ; Layet, Valerie ; Meur, Nathalie Le ; Le Goff, Céline ; Duban-Bedu, Bénédicte ; Sukno, Sylvie ; Boute, Odile ; Andrieux, Joris ; Blanchet, Patricia ; Geneviève, David ; Puechberty, Jacques ; Schneider, Anouck ; Leheup, Bruno ; Jonveaux, Philippe ; Mercier, Sandra ; David, Albert ; Le Caignec, Cédric ; De Pontual, Loic ; Pipiras, Eva ; Jacquette, Aurelia ; Keren, Boris ; Gilbert-Dussardier, Brigitte ; Bilan, Frederic ; Goldenberg, Alice ; Chambon, Pascal ; Toutain, Annick ; Till, Marianne ; Sanlaville, Damien ; Leube, Barbara ; Royer-Pokora, Brigitte ; Grabe, Hans Jörgen ; Schmidt, Carsten Oliver ; Schurmann, Claudia ; Homuth, Georg ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Bernardini, Laura ; Novelli, Antonio ; Micale, Lucia ; Merla, Giuseppe ; Zollino, Marcella ; Mari, Francesca ; Rizzo, Caterina Lo ; Renieri, Alessandra ; Silengo, Margherita ; Vulto-Van Silfhout, Anneke T ; Schouten, Meyke ; Pfundt, Rolph ; De Leeuw, Nicole ; Vansenne, Fleur ; Maas, Saskia M ; Barge-Schaapveld, Daniela Qcm ; Knegt, Alida C ; Stadheim, Barbro ; Rodningen, Olaug ; Houge, Gunnar ; Price, Sue ; Hawkes, Lara ; Campbell, Carolyn ; Kini, Usha ; Vogt, Julie ; Walters, Robin ; Blakemore, Alexandra ; Gusella, James F ; Shen, Yiping ; Scott, Daryl ; Bacino, Carlos A ; Tsuchiya, Karen ; Ladda, Roger ; Sell, Susan ; Asamoah, Alexander ; Hamati, Aline I ; Rosenfeld, Jill A ; Shaffer, Lisa G ; Mitchell, Elyse ; Hodge, Jennelle C ; Beckmann, Jacques S ; Jacquemont, Sébastien ; Reymond, Alexandre ; Ewans, Lisa J ; Mowat, David ; Walker, Jan ; Amor, David J ; Esch, Hilde Van ; Leroy, Patricia ; Bamforth, John-Steven ; Babu, Deepti ; Isidor, Bertrand ; Didonato, Nataliya ; Hackmann, Karl ; Passeggeri, Marzia ; Haeringen, Arie Van ; Smith, Rosemarie ; Ellingwood, Sara ; Farber, Darren M ; Puri, Vinay ; Zadeh, Neda ; Weaver, David D ; Miller, Mandy ; Wilks, Timothy ; Jorgez, Carolina J ; Lafayette, Deedee ; Van Dijck, A ; Kooy, R F ; Sanlaville, D ; Rosenfeld, J A ; Shaffer, L G ; Andrieux, J ; Marshall, C ; Scherer, S W ; Shen, Y ; Gusella, J F ; Thorsteinsdottir, U ; Thorleifsson, G ; Dermitzakis, E T ; Deplancke, B ; Beckmann, J S ; Rougemont, J ; Jacquemont, S ; Reymond, A ; 2p15 Consortium; 16p11 2 Consortium

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts’ maps could uncover functionally and clinically related genes.


Published in:
Molecular Psychiatry, 22, 6, 836-849
Year:
2017
Publisher:
London, Springer Nature
ISSN:
1359-4184
1476-5578
Note:
This article is licensed under a Creative Commons Attribution 4.0 International License
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Note: The status of this file is: Anyone


 Record created 2017-03-31, last modified 2020-07-29

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