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1. Rare copy number variation in posttraumatic stress disorder.

Author

Maihofer, AX, Engchuan, W, Huguet, G, Klein, M, MacDonald, JR, Shanta, O, Thiruvahindrapuram, B, Jean-Louis, M, Saci, Z, Jacquemont, S, Scherer, SW, Ketema, E, Aiello, AE, Amstadter, AB, Avdibegović, E, Babic, D, Baker, DG, Bisson, JI, Boks, MP, Bolger, EA, Bryant, RA, Bustamante, AC, Caldas-de-Almeida, JM, Cardoso, G, Deckert, J, Delahanty, DL, Domschke, K, Dunlop, BW, Dzubur-Kulenovic, A, Evans, A, Feeny, NC, Franz, CE, Gautam, A, Geuze, E, Goci, A, Hammamieh, R, Jakovljevic, M, Jett, M, Jones, I, Kaufman, ML, Kessler, RC, King, AP, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Lugonja, B, Luykx, JJ, Lyons, MJ, Mavissakalian, MR, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Morris, CP, Muhie, S, Orcutt, HK, Peverill, M, Ratanatharathorn, A, Risbrough, VB, Rizzo, A, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rutten, BPF, Schijven, D, Seng, JS, Sheerin, CM, Sorenson, MA, Teicher, MH, Uddin, M, Ursano, RJ, Vinkers, CH, Voisey, J, Weber, H, Winternitz, S, Xavier, M, Yang, R, McD Young, R, Zoellner, LA, Psychiatric Genomics Consortium PTSD Working Group, Psychiatric Genomics Consortium CNV Working Group, Salem, RM, Shaffer, RA, Wu, T, Ressler, KJ, Stein, MB, Koenen, KC, Sebat, J, Nievergelt, CM, Maihofer, AX, Engchuan, W, Huguet, G, Klein, M, MacDonald, JR, Shanta, O, Thiruvahindrapuram, B, Jean-Louis, M, Saci, Z, Jacquemont, S, Scherer, SW, Ketema, E, Aiello, AE, Amstadter, AB, Avdibegović, E, Babic, D, Baker, DG, Bisson, JI, Boks, MP, Bolger, EA, Bryant, RA, Bustamante, AC, Caldas-de-Almeida, JM, Cardoso, G, Deckert, J, Delahanty, DL, Domschke, K, Dunlop, BW, Dzubur-Kulenovic, A, Evans, A, Feeny, NC, Franz, CE, Gautam, A, Geuze, E, Goci, A, Hammamieh, R, Jakovljevic, M, Jett, M, Jones, I, Kaufman, ML, Kessler, RC, King, AP, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Lugonja, B, Luykx, JJ, Lyons, MJ, Mavissakalian, MR, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Morris, CP, Muhie, S, Orcutt, HK, Peverill, M, Ratanatharathorn, A, Risbrough, VB, Rizzo, A, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rutten, BPF, Schijven, D, Seng, JS, Sheerin, CM, Sorenson, MA, Teicher, MH, Uddin, M, Ursano, RJ, Vinkers, CH, Voisey, J, Weber, H, Winternitz, S, Xavier, M, Yang, R, McD Young, R, Zoellner, LA, Psychiatric Genomics Consortium PTSD Working Group, Psychiatric Genomics Consortium CNV Working Group, Salem, RM, Shaffer, RA, Wu, T, Ressler, KJ, Stein, MB, Koenen, KC, Sebat, J, and Nievergelt, CM

Abstract

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.

Published
2022

2. The Effects of Common Structural Variants on {3D} Chromatin Structure

Author

Shanta, O., Noor, A., Sebat, J., Chaisson, M., Sanders, A., Zhao, X., Malhotra, A., Porubsky, D., Rausch, T., Gardner, E., Rodriguez, O., Guo, L., Collins, R., Fan, X., Wen, J., Handsaker, R., Fairley, S., Kronenberg, Z., Kong, X., Hormozdiari, F., Lee, D., Wenger, A., Hastie, A., Antaki, D., Anantharaman, T., Audano, P., Brand, H., Cantsilieris, S., Cao, H., Cerveira, E., Chen, C., Chen, X., Chin, C., Chong, Z., Chuang, N., Lambert, C., Church, D., Clarke, L., Farrell, A., Flores, J., Galeey, T., Gujral, M., Guryev, V., Heaton, W., Korlach, J., Kumar, S., Kwon, J., Lam, E., Lee, J., Lee, W., Lee, S., Li, S., Marks, P., Viaud-Martinez, K., Meiers, S., Munson, K., Navarro, F., Nelson, B., Nodzak, C., Kyriazopoulou-Panagiotopoulou, S., Pang, A., Rosanio, G., Ryan, M., Stuetz, A., Spierings, D., Ward, A., Welch, A., Xiao, M., Xu, W., Zhang, C., Zhu, Q., Zheng-Bradley, X., Lowy, E., Yakneen, S., McCarroll, S., Jun, G., Ding, L., Koh, C., Flicek, P., Chen, K., Gerstein, M., Kwok, P., Lansdorp, P., Marth, G., Shi, X., Bashir, A., Ye, K., Devine, S., Talkowski, M., Mills, R., Marschall, T., Korbel, J., Eichler, E., Lee, C., HGSVC, Intelligent Systems, Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
Cancer Research, DOMAINS, lcsh:QH426-470, CFHR1, lcsh:Biotechnology, Population, Biology, Genome, Structural variation, Chromosome conformation capture, Deletion, 03 medical and health sciences, 0302 clinical medicine, Hi-C, lcsh:TP248.13-248.65, Cell Line, Tumor, Genetics, TAD fusion, Chromosomes, Human, Humans, 1000 Genomes Project, education, Gene, 030304 developmental biology, Sequence Deletion, 0303 health sciences, education.field_of_study, Sequence Inversion, Breakpoint, Inversion, TAD, Chromatin Assembly and Disassembly, Chromatin, GENOME, lcsh:Genetics, Enhancer Elements, Genetic, Genomic Structural Variation, Linear Models, 030217 neurology & neurosurgery, Biotechnology, Research Article
Abstract

Background Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1–1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.

Published
2020

3. Rare copy number variation in posttraumatic stress disorder.

Author

Maihofer AX, Engchuan W, Huguet G, Klein M, MacDonald JR, Shanta O, Thiruvahindrapuram B, Jean-Louis M, Saci Z, Jacquemont S, Scherer SW, Ketema E, Aiello AE, Amstadter AB, Avdibegović E, Babic D, Baker DG, Bisson JI, Boks MP, Bolger EA, Bryant RA, Bustamante AC, Caldas-de-Almeida JM, Cardoso G, Deckert J, Delahanty DL, Domschke K, Dunlop BW, Dzubur-Kulenovic A, Evans A, Feeny NC, Franz CE, Gautam A, Geuze E, Goci A, Hammamieh R, Jakovljevic M, Jett M, Jones I, Kaufman ML, Kessler RC, King AP, Kremen WS, Lawford BR, Lebois LAM, Lewis C, Liberzon I, Linnstaedt SD, Lugonja B, Luykx JJ, Lyons MJ, Mavissakalian MR, McLaughlin KA, McLean SA, Mehta D, Mellor R, Morris CP, Muhie S, Orcutt HK, Peverill M, Ratanatharathorn A, Risbrough VB, Rizzo A, Roberts AL, Rothbaum AO, Rothbaum BO, Roy-Byrne P, Ruggiero KJ, Rutten BPF, Schijven D, Seng JS, Sheerin CM, Sorenson MA, Teicher MH, Uddin M, Ursano RJ, Vinkers CH, Voisey J, Weber H, Winternitz S, Xavier M, Yang R, McD Young R, Zoellner LA, Salem RM, Shaffer RA, Wu T, Ressler KJ, Stein MB, Koenen KC, Sebat J, and Nievergelt CM

Subjects
Humans, Genome, Brain, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, DNA Copy Number Variations, Stress Disorders, Post-Traumatic genetics
Abstract

Posttraumatic stress disorder (PTSD) is a heritable (h 2  = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10 -8 ). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further., (© 2022. The Author(s).)

Published
2022
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4. Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development.

Author

Qiu Y, Arbogast T, Lorenzo SM, Li H, Tang SC, Richardson E, Hong O, Cho S, Shanta O, Pang T, Corsello C, Deutsch CK, Chevalier C, Davis EE, Iakoucheva LM, Herault Y, Katsanis N, Messer K, and Sebat J

Subjects
Chromosome Deletion, Chromosomes, Human, Pair 16 genetics, Female, Humans, Male, Autistic Disorder genetics, Chromosome Disorders genetics, Craniofacial Abnormalities genetics, DNA Copy Number Variations genetics, Intellectual Disability genetics
Abstract

A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2019
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