TY - JOUR
T1 - Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn’s disease
AU - Di Narzo, Antonio
AU - Frades, Itziar
AU - Crane, Heidi M.
AU - Crane, Paul K.
AU - Hulot, Jean Sebastian
AU - Kasarskis, Andrew
AU - Hart, Amy
AU - Argmann, Carmen
AU - Dubinsky, Marla
AU - Peter, Inga
AU - Hao, Ke
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
PY - 2021/6
Y1 - 2021/6
N2 - To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn’s Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10–5). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10–5) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10−3 and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10–3, with the effect independent of CD diagnosis). A pathway analysis of the variants overlapping between PRS-height and PRS-CD detected significant enrichment of genes from the inflammatory, immune-mediated and growth factor regulation pathways. This finding supports the clinical observation of growth failure in patients with childhood-onset CD and demonstrates the value of using individual-level data from dbGaP in searching for shared genetic determinants. This information can help provide a refined insight into disease pathogenesis and may have major implications for novel therapies and drug repurposing.
AB - To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn’s Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10–5). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10–5) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10−3 and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10–3, with the effect independent of CD diagnosis). A pathway analysis of the variants overlapping between PRS-height and PRS-CD detected significant enrichment of genes from the inflammatory, immune-mediated and growth factor regulation pathways. This finding supports the clinical observation of growth failure in patients with childhood-onset CD and demonstrates the value of using individual-level data from dbGaP in searching for shared genetic determinants. This information can help provide a refined insight into disease pathogenesis and may have major implications for novel therapies and drug repurposing.
UR - http://www.scopus.com/inward/record.url?scp=85100145508&partnerID=8YFLogxK
U2 - 10.1007/s00439-020-02250-3
DO - 10.1007/s00439-020-02250-3
M3 - Article
C2 - 33452914
AN - SCOPUS:85100145508
SN - 0340-6717
VL - 140
SP - 865
EP - 877
JO - Human Genetics
JF - Human Genetics
IS - 6
ER -