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Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Shaolei Teng, Pippa A. Thomson, Shane E. McCarthy, Melissa Kramer, Stephanie Muller, Jayon Lihm, Stewart Morris, Dinesh Soares, William Hennah, Sarah Harris, Luiz Miguel Camargo, Vladislav Malkov, Andrew M McIntosh, J. Kirsty Millar, Douglas Blackwood, Kathryn L. Evans, Ian J. Deary, David J. Porteous, W. Richard McCombie
doi: https://doi.org/10.1101/083816
Shaolei Teng
1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
2Department of Biology, Howard University, Washington DC, USA
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Pippa A. Thomson
3Centre for Genomic and Experimental Medicine, MRC/University of Edinburgh Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, UK
4Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK
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Shane E. McCarthy
1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
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Melissa Kramer
1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
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Stephanie Muller
1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
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Jayon Lihm
1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
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Stewart Morris
3Centre for Genomic and Experimental Medicine, MRC/University of Edinburgh Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, UK
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Dinesh Soares
3Centre for Genomic and Experimental Medicine, MRC/University of Edinburgh Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, UK
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William Hennah
5Institute for Molecular Medicine, Finland FIMM, University of Helsinki, Helsinki, Finland
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Sarah Harris
3Centre for Genomic and Experimental Medicine, MRC/University of Edinburgh Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, UK
4Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK
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Luiz Miguel Camargo
6UCB New Medicines, One Broadway, Cambridge, MA, USA
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Vladislav Malkov
7Genetics and Pharmacogenomics, MRL, Merck & Co, Boston, MA, USA
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Andrew M McIntosh
8Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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J. Kirsty Millar
3Centre for Genomic and Experimental Medicine, MRC/University of Edinburgh Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, UK
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Douglas Blackwood
8Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Kathryn L. Evans
4Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK
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Ian J. Deary
4Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK
9Department of Psychology, University of Edinburgh, Edinburgh, UK.
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David J. Porteous
3Centre for Genomic and Experimental Medicine, MRC/University of Edinburgh Institute of Genetics & Molecular Medicine, Western General Hospital, Edinburgh, UK
4Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK
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  • For correspondence: mccombie@cshl.edu david.porteous@ed.ac.uk
W. Richard McCombie
1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
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  • For correspondence: mccombie@cshl.edu david.porteous@ed.ac.uk
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ABSTRACT

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.

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Posted October 27, 2016.
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Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia
Shaolei Teng, Pippa A. Thomson, Shane E. McCarthy, Melissa Kramer, Stephanie Muller, Jayon Lihm, Stewart Morris, Dinesh Soares, William Hennah, Sarah Harris, Luiz Miguel Camargo, Vladislav Malkov, Andrew M McIntosh, J. Kirsty Millar, Douglas Blackwood, Kathryn L. Evans, Ian J. Deary, David J. Porteous, W. Richard McCombie
bioRxiv 083816; doi: https://doi.org/10.1101/083816
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Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia
Shaolei Teng, Pippa A. Thomson, Shane E. McCarthy, Melissa Kramer, Stephanie Muller, Jayon Lihm, Stewart Morris, Dinesh Soares, William Hennah, Sarah Harris, Luiz Miguel Camargo, Vladislav Malkov, Andrew M McIntosh, J. Kirsty Millar, Douglas Blackwood, Kathryn L. Evans, Ian J. Deary, David J. Porteous, W. Richard McCombie
bioRxiv 083816; doi: https://doi.org/10.1101/083816

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