Rationale:
Although HDL-C levels are known to have a complex genetic basis, most studies have focused solely on identifying rare variants with large phenotypic effects to explain extreme HDL-C phenotypes.
Objective:
Here we concurrently evaluate the contribution of both rare and common genetic variants, as well as large-scale copy number variations (CNVs), towards extreme HDL-C concentrations.
Methods:
In clinically ascertained patients with low (
N
=136) and high (
N
=119) HDL-C profiles, we applied our targeted next-generation sequencing panel (LipidSeq
TM
) to sequence genes involved in HDL metabolism, which were subsequently screened for rare variants and CNVs. We also developed a novel polygenic trait score (PTS) to assess patients’ genetic accumulations of common variants that have been shown by genome-wide association studies to associate primarily with HDL-C levels. Two additional cohorts of patients with extremely low and high HDL-C (total
N
=1,746 and
N
=1,139, respectively) were used for PTS validation.
Results:
In the discovery cohort, 32.4% of low HDL-C patients carried rare variants or CNVs in primary (
ABCA1
,
APOA1
,
LCAT
) and secondary (
LPL
,
LMF1
,
GPD1
,
APOE
) HDL-C–altering genes. Additionally, 13.4% of high HDL-C patients carried rare variants or CNVs in primary (
SCARB1
,
CETP
,
LIPC
,
LIPG
) and secondary (
APOC3
,
ANGPTL4
) HDL-C–altering genes. For polygenic effects, patients with abnormal HDL-C profiles but without rare variants or CNVs were ~2-fold more likely to have an extreme PTS compared to normolipidemic individuals, indicating an increased frequency of common HDL-C–associated variants in these patients. Similar results in the two validation cohorts demonstrate that this novel PTS successfully quantifies common variant accumulation, further characterizing the polygenic basis for extreme HDL-C phenotypes.
Conclusions:
Patients with extreme HDL-C levels have various combinations of rare variants, common variants, or CNVs driving their phenotypes. Fully characterizing the genetic basis of HDL-C levels must extend to encompass multiple types of genetic determinants—not just rare variants—to further our understanding of this complex, controversial quantitative trait.
Genetic Analysis of the ZNF804A Gene in Mexican Patients With Schizophrenia, Schizoaffective Disorder and Bipolar Disorder
