Open AccessGenetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study
Author(s) -
Eliana PortillaFernandez,
Derek Klarin,
ShihJen Hwang,
Mary L. Biggs,
Joshua C. Bis,
Stefan Weiß,
Susanne Rospleszcz,
Pradeep Natarajan,
Udo Hoffmann,
Ian S. Rogers,
Quynh A. Truong,
Uwe Völker,
Marcus Dörr,
Robin Bülow,
Michael H. Criqui,
Matthew Allison,
Santhi K. Ganesh,
Jie Yao,
Mélanie Waldenberger,
Fabian Bamberg,
Kenneth Rice,
Jeroen Essers,
Daniek Kapteijn,
Sander W. van der Laan,
R.J. de Knegt,
Mohsen Ghanbari,
Janine F. Felix,
M. Arfan Ikram,
Maryam Kavousi,
André G. Uitterlinden,
Anton J.M. Roks,
A.H. Jan Danser,
Philip S. Tsao,
Scott M. Damrauer,
Xiuqing Guo,
Jerome I. Rotter,
Bruce M. Psaty,
Sekar Kathiresan,
Henry Völzke,
Annette Peters,
Craig Johnson,
Konstantin Strauch,
Thomas Meitinger,
Christopher J. O’Donnell,
Abbas Dehghan
Publication year - 2022
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddac051
Subject(s) - mendelian randomization , genome wide association study , exome , genetic association , biology , abdominal aortic aneurysm , candidate gene , genetics , medicine , exome sequencing , single nucleotide polymorphism , aneurysm , gene , surgery , genotype , mutation , genetic variants
Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of abdominal aortic aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in 10 cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects [Partners Biobank cohort 1 (PBIO)] as replication. Maximum anterior–posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In genome-wide association study (GWAS) on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = −0.02, SE = 0.004, P-value = 2.10 × 10−8). The association replicated in the PBIO1 cohort (P-value = 8.19 × 10−4). In exome-array single-variant analysis (P-value threshold = 9 × 10−7), the lowest P-value was found for rs239259 located in SLC22A20 (beta = 0.007, P-value = 1.2 × 10−5). In the gene-based analysis (P-value threshold = 1.85 × 10−6), PCSK5 showed an association with AAD (P-value = 8.03 × 10−7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = −0.003, P-value = 0.02), triglycerides (beta = −0.16, P-value = 0.008) and height (beta = 0.03, P-value < 0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.