Cross-tissue eQTL enrichment of associations in schizophrenia.

Francesco Bettella (Lead / Corresponding author), Andrew A. Brown, Olav B. Smeland, Yungpeng Wang, Aree Witoelar, Alfonso A. Buil Demur, Wesley K. Thompson, Verena Zuber, Anders M. Dale, Srdjan Djurovic, Ole A. Andreassen

Research output: Contribution to journalArticle

33 Downloads (Pure)

Abstract

The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.
Original languageEnglish
Article numbere0202812
Pages (from-to)1-17
Number of pages17
JournalPLoS ONE
Volume13
Issue number9
DOIs
Publication statusPublished - 6 Sep 2018

Fingerprint

Quantitative Trait Loci
quantitative trait loci
Schizophrenia
Tissue
Nerve Tissue
Neurology
Nervous System
Adipose Tissue
nervous system
Blood Pressure
adipose tissue
Organ Specificity
schizophrenia
tissues
Genome-Wide Association Study
Transcription Initiation Site
Genomics
Blood
Type 2 Diabetes Mellitus
pleiotropy

Cite this

Bettella, F., Brown, A. A., Smeland, O. B., Wang, Y., Witoelar, A., Buil Demur, A. A., ... Andreassen, O. A. (2018). Cross-tissue eQTL enrichment of associations in schizophrenia. PLoS ONE, 13(9), 1-17. [e0202812]. https://doi.org/10.1371/journal.pone.0202812
Bettella, Francesco ; Brown, Andrew A. ; Smeland, Olav B. ; Wang, Yungpeng ; Witoelar, Aree ; Buil Demur, Alfonso A. ; Thompson, Wesley K. ; Zuber, Verena ; Dale, Anders M. ; Djurovic, Srdjan ; Andreassen, Ole A. / Cross-tissue eQTL enrichment of associations in schizophrenia. In: PLoS ONE. 2018 ; Vol. 13, No. 9. pp. 1-17.
@article{96b3f2bf6d5144979051012a35c74985,
title = "Cross-tissue eQTL enrichment of associations in schizophrenia.",
abstract = "The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.",
author = "Francesco Bettella and Brown, {Andrew A.} and Smeland, {Olav B.} and Yungpeng Wang and Aree Witoelar and {Buil Demur}, {Alfonso A.} and Thompson, {Wesley K.} and Verena Zuber and Dale, {Anders M.} and Srdjan Djurovic and Andreassen, {Ole A.}",
year = "2018",
month = "9",
day = "6",
doi = "10.1371/journal.pone.0202812",
language = "English",
volume = "13",
pages = "1--17",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

Bettella, F, Brown, AA, Smeland, OB, Wang, Y, Witoelar, A, Buil Demur, AA, Thompson, WK, Zuber, V, Dale, AM, Djurovic, S & Andreassen, OA 2018, 'Cross-tissue eQTL enrichment of associations in schizophrenia.', PLoS ONE, vol. 13, no. 9, e0202812, pp. 1-17. https://doi.org/10.1371/journal.pone.0202812

Cross-tissue eQTL enrichment of associations in schizophrenia. / Bettella, Francesco (Lead / Corresponding author); Brown, Andrew A.; Smeland, Olav B.; Wang, Yungpeng; Witoelar, Aree; Buil Demur, Alfonso A.; Thompson, Wesley K.; Zuber, Verena; Dale, Anders M.; Djurovic, Srdjan; Andreassen, Ole A.

In: PLoS ONE, Vol. 13, No. 9, e0202812, 06.09.2018, p. 1-17.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cross-tissue eQTL enrichment of associations in schizophrenia.

AU - Bettella, Francesco

AU - Brown, Andrew A.

AU - Smeland, Olav B.

AU - Wang, Yungpeng

AU - Witoelar, Aree

AU - Buil Demur, Alfonso A.

AU - Thompson, Wesley K.

AU - Zuber, Verena

AU - Dale, Anders M.

AU - Djurovic, Srdjan

AU - Andreassen, Ole A.

PY - 2018/9/6

Y1 - 2018/9/6

N2 - The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.

AB - The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10−06), epidermal (β = 0.12, p = 3.1 × 10−04), lymphoblastoid (β = 0.19, p = 6.2 × 10−08) and blood (β = 0.19, p = 6.4 × 10−06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.

UR - http://europepmc.org/abstract/med/30188921

U2 - 10.1371/journal.pone.0202812

DO - 10.1371/journal.pone.0202812

M3 - Article

VL - 13

SP - 1

EP - 17

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

M1 - e0202812

ER -

Bettella F, Brown AA, Smeland OB, Wang Y, Witoelar A, Buil Demur AA et al. Cross-tissue eQTL enrichment of associations in schizophrenia. PLoS ONE. 2018 Sep 6;13(9):1-17. e0202812. https://doi.org/10.1371/journal.pone.0202812