Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors

Ole A Andreassen; Srdjan Djurovic; Wesley K Thompson; Andrew J Schork; Kenneth S Kendler; Michael C O'Donovan; Dan Rujescu; Thomas Werge; Martijn van de Bunt; Andrew P Morris; Mark I McCarthy; J Cooper Roddey; Linda K McEvoy; Rahul S Desikan; Anders M Dale; International Consortium for Blood Pressure GWAS

doi:10.1016/j.ajhg.2013.01.001

Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors

Ole A Andreassen, Srdjan Djurovic, Wesley K Thompson, Andrew J Schork, Kenneth S Kendler, Michael C O'Donovan, Dan Rujescu, Thomas Werge, Martijn van de Bunt, Andrew P Morris, Mark I McCarthy, J Cooper Roddey, Linda K McEvoy, Rahul S Desikan, Anders M Dale, International Consortium for Blood Pressure GWAS

245 Citationer (Scopus)

Abstract

Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.

Originalsprog	Engelsk
Tidsskrift	American Journal of Human Genetics
Vol/bind	92
Udgave nummer	2
Sider (fra-til)	197-209
Antal sider	13
ISSN	0002-9297
DOI	https://doi.org/10.1016/j.ajhg.2013.01.001
Status	Udgivet - 7 feb. 2013

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10.1016/j.ajhg.2013.01.001

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Andreassen, O. A., Djurovic, S., Thompson, W. K., Schork, A. J., Kendler, K. S., O'Donovan, M. C., Rujescu, D., Werge, T., van de Bunt, M., Morris, A. P., McCarthy, M. I., Roddey, J. C., McEvoy, L. K., Desikan, R. S., Dale, A. M., & International Consortium for Blood Pressure GWAS (2013). Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors. American Journal of Human Genetics, 92(2), 197-209. https://doi.org/10.1016/j.ajhg.2013.01.001

Andreassen, OA, Djurovic, S, Thompson, WK, Schork, AJ, Kendler, KS, O'Donovan, MC, Rujescu, D, Werge, T, van de Bunt, M, Morris, AP, McCarthy, MI, Roddey, JC, McEvoy, LK, Desikan, RS, Dale, AM & International Consortium for Blood Pressure GWAS 2013, 'Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors', American Journal of Human Genetics, bind 92, nr. 2, s. 197-209. https://doi.org/10.1016/j.ajhg.2013.01.001

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title = "Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors",

abstract = "Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the {"}missing heritability{"} of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this {"}pleiotropic enrichment{"} by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.",

author = "Andreassen, {Ole A} and Srdjan Djurovic and Thompson, {Wesley K} and Schork, {Andrew J} and Kendler, {Kenneth S} and O'Donovan, {Michael C} and Dan Rujescu and Thomas Werge and {van de Bunt}, Martijn and Morris, {Andrew P} and McCarthy, {Mark I} and Roddey, {J Cooper} and McEvoy, {Linda K} and Desikan, {Rahul S} and Dale, {Anders M} and Thomas Werge",

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doi = "10.1016/j.ajhg.2013.01.001",

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T1 - Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors

AU - Andreassen, Ole A

AU - Djurovic, Srdjan

AU - Thompson, Wesley K

AU - Schork, Andrew J

AU - Kendler, Kenneth S

AU - O'Donovan, Michael C

AU - Rujescu, Dan

AU - Werge, Thomas

AU - van de Bunt, Martijn

AU - Morris, Andrew P

AU - McCarthy, Mark I

AU - Roddey, J Cooper

AU - McEvoy, Linda K

AU - Desikan, Rahul S

AU - Dale, Anders M

AU - International Consortium for Blood Pressure GWAS

PY - 2013/2/7

Y1 - 2013/2/7

N2 - Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.

AB - Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.

U2 - 10.1016/j.ajhg.2013.01.001

DO - 10.1016/j.ajhg.2013.01.001

M3 - Journal article

C2 - 23375658

SN - 0002-9297

VL - 92

SP - 197

EP - 209

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors

Abstract

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