A Custom Global Screening Array for Integrated Familial Hypercholesterolemia Detection and Polygenic Risk Assessment in a Multi-Ethnic New Zealand Population
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Background
Cardiovascular disease (CVD) is the leading cause of mortality in New Zealand, with significant inequities affecting Māori and Pacific peoples. Familial hypercholesterolemia (FH) affects approximately 1 in 313 individuals globally, yet over 90% remain undiagnosed. Standard polygenic risk scores (PRS) derived from European cohorts may not be portable to diverse ancestries. We developed the Holo-Q Omniscan Waka Te Ira, a custom Illumina Global Screening Array (GSA) v3 enriched with FH mutations, CAD PRS markers, and network medicine-derived epistasis content.
Methods
Holo-Q Omniscan Waka Te Ira was developed as a customized version of the Illumina Global Screening Array v3, adding 43,437 SNPs targeting familial hypercholesterolaemia and coronary artery disease. Variants in the three primary FH genes were collected from a regional diagnostic laboratory list, published literature, ClinVar, and the Leiden Open Variation Database, resulting in 6,717 unique SNPs. Additional content included 14,005 pathogenic or likely pathogenic variants from cardiovascular, lipid-related genes and 12 pharmacogenes; and 5,845 probes supporting copy number variant detection. The array further incorporated 5,232 network medicine–derived coronary artery disease SNPs and 14,806 rare variants from a validated multi-ancestry polygenic score. To improve ancestral representation, 289 variants specific to New Zealand, European, Asian, and African populations, along with 118 variants specific to populations from Japan, Korea, Thailand, and Russia were added. Validation was performed using large-scale genotype and whole-genome sequencing datasets with polygenic score benchmarking. The completed design contained 47,027 SNPs overall, including 3,590 loci inherited from the GSA v3 backbone and 43,437 newly incorporated through custom content expansion.
Results
Approximately half of the newly added SNPs were observed in a large European-ancestry dataset, with high recovery for common polygenic score loci but low recovery for population-specific founder variants. The array captured 938 (84%) of all unique pathogenic or likely pathogenic familial hypercholesterolaemia variants catalogued in ClinVar at the time of design, representing a 26.4% expansion beyond the standard backbone array. Whole-genome sequencing validation identified additional carriers of rare high-impact variants present only in the custom content. The selected coronary artery disease polygenic score model achieved an adjusted area under the receiver operating characteristic curve of 0.786. Together, these results demonstrate enhanced monogenic detection, robust polygenic performance, and improved representation of ancestrally diverse populations within a single screening platform.
Conclusion
The Holo-Q Omniscan Waka Te Ira enhances detection of clinically relevant FH variants and provides robust PRS coverage. The low recovery of population-specific alleles in UK datasets underscores the necessity of this custom array for equitable genomic medicine in New Zealand’s multi-ethnic population.
