rs1048661

mixedMag 7.5

This is a protein-altering variant in the LOXL1 gene.

Key Literature Trait Associations

Exfoliation Glaucoma

rs1048661 encodes the R141L amino acid change in exon 1 of LOXL1, a lysyl oxidase-like enzyme essential for cross-linking elastin and collagen fibers in the extracellular matrix. The G allele (risk in Europeans) disrupts normal elastin fiber assembly in the trabecular meshwork and lens capsule, promoting accumulation of exfoliative fibrillar material. Affected individuals progress to exfoliation glaucoma through elevated intraocular pressure caused by trabecular meshwork obstruction. Notably, the risk allele reverses in East Asian populations, where the T allele confers markedly elevated risk.

Thorleifsson G et al. “Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.” Science (new York, N.y.) 317(5843):1397-1400 (2007)

Allele G

OR 1.99

p 2.3e-12

Large GWAS

Li X et al. “LOXL1 gene polymorphisms are associated with exfoliation syndrome/exfoliation glaucoma risk: An updated meta-analysis.” Plos One (2021)

Allele G

OR —

p —

N 13,984

Meta-analysis

multi-ancestry

Tang JZ et al. “Association between polymorphisms in lysyl oxidase-like 1 and susceptibility to pseudoexfoliation syndrome and pseudoexfoliation glaucoma.” Plos One (2014)

Allele G

OR —

p —

N 3,600

Preliminary work

multi-ancestry

“Ethnicity-Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma”

Allele G

OR —

p —

Candidate gene study

multi-ancestry

Wang L et al. “LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma: A Meta-Analysis.” Journal of Glaucoma (2016)

Allele G

OR —

p —

Meta-analysis

multi-ancestry

Descending aorta diameter

The G allele of rs1048661 is associated with smaller descending aortic diameter at genome-wide significance in large European GWAS. Two independent studies (n=34,532 and n=32,590) replicate this signal with beta values of ~0.035–0.039 SD units per allele. The association is mechanistically plausible given LOXL1's role in elastin cross-linking and aortic wall structural integrity. Effect sizes are modest and the clinical significance for individual risk is limited, though the finding underscores LOXL1's broader role in connective tissue homeostasis beyond the eye.

Pirruccello JP et al. “Deep learning enables genetic analysis of the human thoracic aorta.” Nature Genetics 54(1):40-51 (2022)

Allele G

OR —

β 0.040

p 1.0e-10

N 39,688

Large GWAS

European

Francis CM et al. “Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.” Nature Communications 13(1):4505 (2022)

Allele G

OR —

β 0.035 ±0.006

p 6.0e-10

N 32,590

Large GWAS

European

Carpal tunnel syndrome

The T allele of rs1048661 is associated with modestly higher risk of carpal tunnel syndrome (CTS) at genome-wide significance (p=8×10⁻¹⁰, OR≈1.046 per T allele, or equivalently the G allele is protective with OR=0.956) in a large European meta-analysis of ~1.24 million individuals. The association is consistent with LOXL1's role in extracellular matrix and connective tissue remodeling, which underlies CTS pathophysiology. The effect size is small and the association is likely a secondary pleotropic signal from LOXL1's broader connective tissue function.

Skuladottir AT et al. “A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.” Nature Communications 13(1):1598 (2022)

Allele G

OR 0.96

p 8.0e-10

N 1,239,680

Meta-analysisLarge GWAS

European

Grip strength

The G allele of rs1048661 is associated with slightly lower hand grip strength at genome-wide significance (beta=-0.012 SD, p=2×10⁻¹⁵) in a large UK Biobank study of over 400,000 European individuals. The effect is small and may reflect LOXL1's role in musculoskeletal connective tissue function, including tendon and ligament collagen/elastin cross-linking. This association is unlikely to be clinically actionable at the individual level given the modest effect size.

Schoeler T et al. “Combining cross-sectional and longitudinal genomic approaches to identify determinants of cognitive and physical decline.” Nature Communications 16(1):4524 (2025)

Allele G

OR —

β -0.012

p 2.0e-15

N 404,112

Large GWAS

European

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GWAS Catalog Trait Associations (4)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

Risk Factor

1 submitter3 publications

Exfoliation syndrome, susceptibility to

View on ClinVar →

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Research that mentions this SNP (2)

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An Investigation Into LOXL1 Variants in Black South African Individuals With Exfoliation Syndrome

AssociationN=90Rautenbach RM et al.(2011)· Archives of Ophthalmology

This case-control study examined two LOXL1 gene variants (rs1048661 R141L and rs3825942 G153D) in 43 black South African patients with exfoliation syndrome (XFS) and 47 ethnically matched controls. Both SNPs were significantly associated with XFS (P=0.00582 and P<0.00001, respectively), but notably the AA genotype of G153D (odds ratio 17.10, 95% CI 4.91-59.56) was the primary risk genotype, contrasting with other populations where the GG genotype conferred risk.

Traits studied:Exfoliation glaucomaExfoliation syndrome

PubMed DOI Metascience Observatory

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Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

ReviewJürgen Brockmöller et al.(2008)· European Journal of Clinical Pharmacology

This comprehensive review article traces the evolution of pharmacogenetics from single-gene analysis to whole-genome approaches. It discusses validated pharmacogenetic biomarkers with clinical impact including CYP2D6, CYP2C9, CYP2C19, TPMT, DPD, VKORC1, UGT1A1, and ADRB1/ADRB2, providing examples of how genetic variants affect drug metabolism and response. The paper emphasizes the importance of integrating pharmacogenetic information into clinical practice and drug development.

Traits studied:5-fluorouracil toxicityanticoagulant responseantidepressant responseasthmaatrial fibrillationbeta-blocker responsebreast cancerclopidogrel responsecolorectal cancerdrug metabolismdrug responsehypertensionirinotecan toxicitylung cancerproton pump inhibitor metabolismrheumatoid arthritisthiopurine toxicitythrombosis risktype 2 diabeteswarfarin sensitivity

rs1048661

Key Literature Trait Associations

Exfoliation Glaucoma

Descending aorta diameter

Carpal tunnel syndrome

Grip strength

GWAS Catalog Trait Associations (4)

ClinVar annotation

Research that mentions this SNP (2)

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