Large-scale genome-wide interaction analyses on multiple cardiometabolic risk factors to identify age-specific genetic risk factors

medRxiv

Abstract

Abstract Background The genetic landscape of cardiometabolic risk factors has been explored extensively. However, insight in the effects of genetic variation on these risk factors over the life course is sparse. Here, we performed genome-wide interaction studies (GWIS) on different cardiometabolic risk factors to identify age-specific genetic risks. Methods This study included 270,276 unrelated European-ancestry participants from the UK Biobank (54.2% women, a median age of 58 [interquartile range (IQR): 50, 63] years). GWIS models with interaction terms between genetic variants and age were performed on apolipoprotein B (ApoB), low-density lipoprotein-cholesterol (LDL-C), log-transformed triglycerides (TG), body mass index (BMI), and systolic blood pressure (SBP). Replication was subsequently performed in the Copenhagen General Population Study (CGPS) and the Estonian Biobank (EstBB). Results Multiple lead variants were identified to have genome-wide significant interactions with age ( P interaction <1e-08). In detail, rs429358 (tagging APOE4 ) was identified for ApoB ( P interaction = 9.0e-14) and TG ( P interaction = 5.4e-16). Three additional lead variants were identified for ApoB: rs11591147 (R46L in PCSK9 , P interaction = 3.9e-09), rs34601365 (near APOB , P interaction = 8.4e-09), and rs17248720 (near LDLR , P interaction = 2.0e-09). Effect sizes of the identified lead variants were generally closer to the null with increasing age. No variant-age interactions were identified for LDL-C, SBP and BMI. The significant interactions of rs429358 with age on ApoB and TG were replicated in both CGPS and EstBB. Conclusions The majority of genetic effects on cardiometabolic risk factors remains relatively constant over age, with the noted exceptions of specific genetic effects on ApoB and TG.

Authors 8

1. Linjun Ao corresponding Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

2. Diana van Heemst
   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden, the Netherlands

3. Jiao Luo

   Copenhagen University Hospital · Rigshospitalet

   Affiliation as printed

   Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark

4. Maris Teder‐Laving

   University of Tartu

   Affiliation as printed

   Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia

5. Reedik Mägi

   University of Tartu

   Affiliation as printed

   Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia

6. Ruth Frikke‐Schmidt

   University of Copenhagen · Herlev Hospital · Copenhagen University Hospital · Gentofte Hospital · Rigshospitalet

   Affiliation as printed

   Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark

   Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

   The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark

7. Ko Willems van Dijk Aachen Department of Human Genetics Department of Internal Medicine Division of Endocrinology, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

   Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands

   Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

8. Raymond Noordam
   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden, the Netherlands