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

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.

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Publication Details

Journal
Human Genomics
Published
2025-11-24
DOI
https://doi.org/10.1186/s40246-025-00831-9
Primary Topic
Lipoproteins and Cardiovascular Health
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Míriam Barrabés, Carlos Alberto Aguilar-Salinas, Babak Moatamed, Alexander Ioannidis et al.
Human Genomics
Lipoproteins and Cardiovascular Health
article

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

Míriam Barrabés, Carlos Alberto Aguilar-Salinas, Babak Moatamed, Alexander Ioannidis, Daniel Elías-López, Roopa Mehta, Alexandro J. Martagón, Consuelo D. Quinto-Cortés, Carlos D. Bustamante, Niki Mourtzi, Nicholas Katsanis, Gabriela A. Galán-Ramírez, Jeffrey D. Wall, David Bonet, Paula Fernández, Daniel Mas Montserrat, Ming Ta Michael Lee, Mohammad Ali Faghihi, Sonia Moreno–Grau, Arturo López Pineda, Rafael Zubirán, Francisco M. De La Vega, Jeff Gulcher, Teresa Tusié‐Luna
article en

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.

Human GenomicsVol. 19(1)
United States Department of Commerce (US), University of California, Santa Cruz (US), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX), Universidad de Morelia (MX), FORTH Institute of Molecular Biology and Biotechnology (GR), Galena Biopharma (United States) (US), Institute of Molecular Biology and Biotechnology (BG), Universidad Latina de América (MX), The University of Texas at Austin (US), Universidad Nacional Autónoma de México (MX), Stanford University (US), Tecnológico de Monterrey (MX)
Amgen
Openalex Percentile: Top 45%
Lipoproteins and Cardiovascular Health
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