TY - JOUR
T1 - Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
AU - Porcu, Eleonora
AU - Rüeger, Sina
AU - Lepik, Kaido
AU - Agbessi, Mawussé
AU - Ahsan, Habibul
AU - Alves, Isabel
AU - Andiappan, Anand
AU - Arindrarto, Wibowo
AU - Awadalla, Philip
AU - Battle, Alexis
AU - Beutner, Frank
AU - Jan Bonder, Marc
AU - Boomsma, Dorret
AU - Christiansen, Mark
AU - Claringbould, Annique
AU - Deelen, Patrick
AU - Esko, Tõnu
AU - Favé, Marie Julie
AU - Franke, Lude
AU - Frayling, Timothy
AU - Gharib, Sina A.
AU - Gibson, Gregory
AU - Heijmans, Bastiaan T.
AU - Hemani, Gibran
AU - Jansen, Rick
AU - Kähönen, Mika
AU - Kalnapenkis, Anette
AU - Kasela, Silva
AU - Kettunen, Johannes
AU - Kim, Yungil
AU - Kirsten, Holger
AU - Kovacs, Peter
AU - Krohn, Knut
AU - Kronberg-Guzman, Jaanika
AU - Kukushkina, Viktorija
AU - Lee, Bernett
AU - Lehtimäki, Terho
AU - Loeffler, Markus
AU - Marigorta, Urko M.
AU - Mei, Hailang
AU - Milani, Lili
AU - Montgomery, Grant W.
AU - Müller-Nurasyid, Martina
AU - Nauck, Matthias
AU - Nivard, Michel
AU - Penninx, Brenda
AU - Veldink, Jan H.
AU - Deelen, Patrick
AU - van den Berg, Leonard H.
AU - Veldink, Jan H.
PY - 2019/7/24
Y1 - 2019/7/24
N2 - Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
AB - Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
KW - Brain Diseases/genetics
KW - GTP-Binding Protein gamma Subunits
KW - Gene Expression Profiling
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Genome-Wide Association Study
KW - Humans
KW - Mendelian Randomization Analysis
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait Loci
KW - Transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85069729041&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10936-0
DO - 10.1038/s41467-019-10936-0
M3 - Article
C2 - 31341166
AN - SCOPUS:85069729041
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3300
ER -