A genome-wide scan for pleiotropy between bone mineral density and nonbone phenotypes

Area of Science:

• Genetics
• Metabolic Bone Disorders
• Genomics

Background:

• Osteoporosis is a global metabolic bone disorder characterized by skeletal fragility.
• Genetic pleiotropy, where one gene influences multiple traits, is crucial for understanding complex diseases.
• Identifying pleiotropic loci for bone mineral density (BMD) can illuminate shared biological pathways with other conditions.

Purpose of the Study:

• To identify pleiotropic genetic loci associated with bone mineral density (BMD) and non-bone phenotypes using genome-wide association studies.
• To investigate shared genetic underpinnings between skeletal fragility and other diseases or traits.

Main Methods:

• Searched the NHGRI-EBI Catalog for genome-wide significant associations (P < 5 × 10⁻⁸) excluding bone phenotypes.
• Used SNiPA to identify proxy single nucleotide polymorphisms (SNPs) and assessed their association with femoral neck (FN) and lumbar spine (LS) BMD data from the GEFOS Consortium.
• Replicated findings in over 400,000 UK Biobank participants, examining genetic markers for BMD and heel bone ultrasound data.

Main Results:

• Identified 72 BMD-related pleiotropic SNPs in the discovery stage.
• Replicated 12 SNPs in 11 loci across 8 chromosomes in the UK Biobank cohort.
• These 12 SNPs were associated with BMD and 14 other distinct phenotypes, including dermatological, allergic, and gastroenterological conditions, as well as magnesium levels.

Conclusions:

• Twelve genome-wide significant SNPs associated with BMD demonstrate pleiotropy with non-bone phenotypes.
• These pleiotropic associations, such as rs479844 and rs4072037, highlight shared genetic mechanisms between bone health and other diseases.
• Understanding these pleiotropic effects can deepen the genetic insights into bone-related disorders and their comorbidities.