RT Journal Article
SR Electronic
T1 Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 083816
DO 10.1101/083816
A1 Shaolei Teng
A1 Pippa A. Thomson
A1 Shane E. McCarthy
A1 Melissa Kramer
A1 Stephanie Muller
A1 Jayon Lihm
A1 Stewart Morris
A1 Dinesh Soares
A1 William Hennah
A1 Sarah Harris
A1 Luiz Miguel Camargo
A1 Vladislav Malkov
A1 Andrew M McIntosh
A1 J. Kirsty Millar
A1 Douglas Blackwood
A1 Kathryn L. Evans
A1 Ian J. Deary
A1 David J. Porteous
A1 W. Richard McCombie
YR 2016
UL http://biorxiv.org/content/early/2016/10/27/083816.abstract
AB 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.