Abstract
Background: Most lipid-associated genetic variants were discovered in European-ancestry cohorts, and Arab populations remain under-represented. Earlier Gulf studies reported low replication of these variants but did not compare the observed replication with the replication expected from the statistical power of the smaller Arab studies. We quantified how well European-ancestry lipid loci transfer to Qatari Arabs.
Methods: This cross-ancestry genetic association study used public summary statistics only. European-ancestry index variants for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and total cholesterol (TC) were taken from the Global Lipids Genetics Consortium 2021 (n = 1,320,016). They were matched to the 2021 Qatar Biobank whole-genome sequencing genome-wide association study (n = 5,972 to 6,017). For each trait we estimated directional concordance, nominal and Bonferroni replication against power-based expectations, an inverse-variance-weighted effect-size slope, between-ancestry heterogeneity and the variance explained by a European-weighted score. We fine-mapped overlapping genome-wide significant Qatari loci with Wakefield approximate Bayes factors under a single-causal-variant assumption. Reporting followed STREGA.
Results: Of 1,600 catalogued index variants, 1,087 variant-trait pairs were analysable. Directional concordance ranged from 69.5% (LDL-C) to 75.1% (HDL-C), below the 77.3% to 80.2% expected under full transfer. Nominal replication was lower than expected for LDL-C (29 vs 42.9; ratio 0.68), TG (23 vs 44.7; ratio 0.51) and TC (36 vs 47.6; ratio 0.76), whereas Bonferroni-significant replication matched expectation (5 to 7 variants per trait). Qatari effects were attenuated relative to European effects for TC (slope 0.88, 95% CI 0.78–0.97), HDL-C (0.78, 0.68–0.88) and TG (0.72, 0.64–0.81); for LDL-C the slope was 0.90 (0.80–1.00), with an interval that reached 1. The European-weighted score explained 6.46% of LDL-C variance (relative to expectation 0.82, 95% CI 0.66–0.99), 5.63% of TC (0.77), 4.13% of TG (0.53) and 3.57% of HDL-C (0.60). Among 16 single-signal Qatari loci, the median 95% credible set contained 6 variants; APOE rs7412 and GCKR rs1260326 resolved to single variants. Five low-frequency multi-signal loci on chromosome 11q23 were excluded from fine-mapping; their pattern is consistent with, but does not establish, an extended Qatari haplotype. These score estimates assume independent variants and are not individual-level validation; TC attenuation was not retained at 5 Mb distance pruning.
Conclusions: European-ancestry lipid loci showed directionally concordant associations in Qatari Arabs, with lower effect-size slopes for HDL-C and TG. Summary-derived score variance estimates are conditional on independence and harmonised trait scales; they are not validated individual-level predictive performance. Findings support Arab-inclusive discovery and local validation before clinical use.
Keywords
- genome-wide association study
- lipids
- polygenic score
- transferability
- fine-mapping
- Qatar
- Arabs
Declarations
- Ethics approval
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- Funding
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- Competing interests
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- Author contributions
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- Data availability
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- Registration
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- Acknowledgements
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