The FP7 funded GEFOS consortium identified a range of BMD-related loci by GWAS (1). This Horizon 2020 application (PI Fernando Rivadeneira, Erasmum Medical Centre, Netherlands) represents an extension of this program, intended to identify further BMD related loci by harnessing whole gemome sequencing technology. It is intended that ALSPAC will contribute to work package (WP) 2, 3 and 6.

In WP2, a musculoskeletal (MSK) chip with GWAS and customized content, which after genotyping ~60,000 young and elderly individuals from 36 studies previously involved in GEFOS (mostly European), will allow the discovery of common, less frequent and rare variants; together with fine mapping of gene regions associated with traits and pathological conditions of the MSK system including BMD, fracture risk, sarcopenia and frailty. ALSPAC mothers will form part of a replication cohort for novel genotype-BMD associations arising from this MSK chip.

In WP3, BMD associated variants will be analysed in relation to different endophenotypes, based on our previous studies suggesting different genetic influences on trabecular and cortical bone (2-4). Associations will be analysed between genetic markers of interest and cortical bone phenotypes obtained in ALSPAC off spring as measured by tibial pQCT, and trabecular bone phenotypes as obtained in ALSPAC mothers by radial pQCT.

In WP6, genetic influences on BMD identified in WP2 will be examined using a lifecourse approach, by comparing the strength of associations (as reflected by beta coefficients) across different times of life. Results from ALSPAC offspring (total body DXA at age 9 and 17, hip DXA at 13 and 17), and ALSPAC mothers (pre versus postmenopausal hip BMD) will contribute to these analyses.

It is envisaged that ALSPAC genetic data will be in the form of genome wide data imputed to 1000 genomes, as previously obtained. In the case of rare variants of interest which are not covered by imputation, there may be a need for custom genotyping. Bone outcomes will comprise DXA and pQCT measures as previously obtained in ALSPAC off spring and mothers.