| Title: | Analysis of a deeply-phenotyped familial hypercholesterolemia cohort from Mexico shows a role for both rare and common alleles across known dyslipidemia genes and reveals structural variation in a novel locus |
| Journal: | Human Genomics |
| Published: | 24 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41287107/ |
| DOI: | https://doi.org/10.1186/s40246-025-00831-9 |
| URL: | https://humgenomics.biomedcentral.com/counter/pdf/10.1186/s40246-025-00831-9 |
Publication 18801
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Abstract
Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in all known FH genes, together with variants in APOE, CREB3L3, and PLIN1, contribute to a molecular FH diagnosis in 67% of families, including novel gene-disruptive copy number variants (CNVs) which arose in a native American background. Second, ancestry-adjusted polygenic risk score analysis identified a significant liability for coronary artery disease, hypertension, LDL, HDL, and Type 2 Diabetes. The polygenic signal for LDL was present in patients with rare, pathogenic FH mutations and was more prominent in individuals bereft of a molecular FH diagnosis. Finally, we report both a whole-gene duplication and common, non-coding variants in a novel locus, PDZK1, which contribute to the genetic burden of FH, a finding we replicated in the UK Biobank (UKB). Together, our analyses illustrate the value of genetic studies in non-European populations and reinforce the notion that individual risk to disease can arise from both rare, large effect alleles (alone or in combination across genes) and common variants that increase the mutational burden of a biological system.</p>
13 Keywords
- Adult
- Alleles
- Cohort Studies
- DNA Copy Number Variations
- Dyslipidemias
- Female
- Genetic Predisposition to Disease
- Humans
- Hyperlipoproteinemia Type II
- Male
- Mexico
- Middle Aged
- Phenotype
24 Authors
- Nicholas Katsanis
- Niki Mourtzi
- Consuelo D. Quinto-Cortés
- Alexandro J. Martagon
- Alexander G. Ioannidis
- Francisco M. De La Vega
- Jeff Gulcher
- Ming Ta Michael Lee
- Mohammad A. Faghihi
- Arturo Lopez-Pineda
- Sonia Moreno-Grau
- Daniel Mas Montserrat
- Míriam Barrabés
- David Bonet
- Pavel Salazar Fernandez
- Jeff Wall
- Babak Moatamed
- Roopa Mehta
- Gabriela A. Galan-Ramirez
- Rafael Zubirán
- Daniel Elias-Lopez
- Teresa Tusié-Luna
- Carlos A. Aguilar-Salinas
- Carlos D. Bustamante
1 Application
| Application ID | Title |
|---|---|
| 89006 | Comparison of the genetic architecture between Latino and UKBB populations as strategy to understand its role on human health traits and diseases. |
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