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Allelic expression imbalance of the schizophrenia susceptibility gene CHI3L1: evidence of cis-acting variation and tissue specific regulation

Hill, Matthew Jamesa; Kenny, Elainea; Roche, Siobhanb; Morris, Derek W.a; Corvin, Aidena; Hawi, Ziariha; Gill, Michaela; Anney, Richard J.L.a

doi: 10.1097/YPG.0b013e328348045b
Original Articles

Objective: To identify cis-acting regulatory variants influencing the expression of the schizophrenia susceptibility gene chitinase 3-like 1 gene (CHI3L1) in human lymphoblasts and post-mortem brain tissue.

Methods: To investigate the role of cis-acting regulatory variants in controlling gene expression of CHI3L1 we quantified relative allelic abundance in individuals heterozygous for the transcribed polymorphism rs880633. Allelic quantification was performed using RNA derived from 45 individuals from the HapMap CEU panel and 41 postmortem brain samples. Association of allelic imbalance with genetic variants was determined at a gene-wide level for the HapMap samples using available genotyping data.

Results: Expression of the CHI3L1 transcript is under the control of potently acting cis-variation in lymphoblasts. Polymorphisms in the promoter region of CHI3L1 were significantly associated with this allelic imbalance. In the single postmortem brain tissue investigated, only moderate allelic imbalance was detected and was restricted to a small number of individuals.

Conclusion: CHI3L1 contains common cis-acting regulatory variants that affect gene expression in lymphoblasts. A previously identified schizophrenia susceptibility variant was significantly associated with allelic imbalance in lymphoblasts. These findings do not support the notion that the schizophrenia-associated CHI3L1 variants influence gene expression in BA46 of the adult brain. We confirm that CHI3L1 contains cis-acting variation but is subject to tissue-specific regulation.

aNeuropsychiatric Genetics Research Group, Trinity College Dublin, Institute of Molecular Medicine

bSmurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland

Present address: Matthew James Hill, Centre for the Cellular Basis of Behaviour, Department of Neuroscience, The James Black Centre, Institute of Psychiatry, Kings College London, 125 Coldharbour Lane, London, SE5 9NU, UK.

Correspondence to Matthew James Hill, PhD, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Institute of Molecular Medicine, Dublin D8, Ireland Tel: +44 20 7848 0821; fax: +44 20 75480986; e-mail:

Received September 14, 2010

Accepted March 6, 2011

© 2011 Lippincott Williams & Wilkins, Inc.