Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Abstract

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

“…However, precision medicine by deep genetic analysis helps improving the diagnosis and the management of patients. An application of genome sequencing in relation to lipid traits was recently published highlighting that this approach can identify new causative loci, new variants in gene-regions usually not analyzed and can be even used to evaluate PRS [ 86 ].…”

Prevalence and risk factors of diabetic peripheral neuropathy: A population‐based cross‐sectional study in China

“…Blood lipids are complex traits that are influenced by genetics, the environment, and the gene-environment interaction. 44,45 Hence, populations with different genetics might display different phenotypes, 44 especially considering the important differences in diet between China and western countries. 46 However, previous studies also reported contrary results regarding the relationship between BMI and DPN.…”

Unravelling the genetic architecture of human complex traits through whole genome sequencing

“…Despite the description of several associations with rare variants, it is still unclear how much they contribute to the heritability of human complex traits. This proportion is especially hard to estimate for rare variants as they correspond to observations only in a few individuals resulting in high standard errors 10 . As common variants are present in more individuals, it is expected that they will contribute more to the phenotypic variance than rare variants.…”

“…For example, an intronic variant of TNRC18 strongly associated with IBD but almost absent from other European populations 20 . WGS in diverse populations represents one of the most active areas of research, as getting an overview of the genetic architecture in diverse populations will enable better comprehension of complex diseases as well as the differences in effect direction and sizes of the associated variants that are observed across populations 10 .…”

“…Furthermore, power to detect associations can be boosted by studying isolated populations, in which variant frequencies and effect sizes may be larger 8 , 18 , 20 . As the majority of WGS projects to date have been focused on European populations, conducting sequencing-based studies in under-represented populations is expected to be of benefit 10 and represents an important direction for future WGS applications.…”