Background

Understanding of the genetic determinants of osteoporosis has recently been advanced by GWAS studies looking at associations with bone mineral density (BMD) in adults (1,2), an approach we have recently applied to ALSPAC (Timpson et al, submitted for publication). However, one of the limitations of these studies is that whereas BMD is related to the risk of osteoporotic fracture in later life, this parameter does not take account of other characteristics of the skeleton which also contribute to fracture risk, such as cortical geometry. In contrast to conventional DXA scanners, pQCT, which has been obtained in all available ALSPAC children at age 16 and is currently being repeated at age 18, can accurately measure cortical bone geometry.

Aims

We plan to conduct the first GWAS analysis of cortical bone geometry, based on pQCT data obtained in ALSPAC children.

Methods

1. GWAS analysis will be performed between results of illumina chip whole genome analysis and pQCT as measured at age 16, in all available ALSPAC children (expect around 800 with 317k chip and 800 with 610k chip). Summary statistics (beta coefficients and P values) will be derived for associations with tibial cortical BMD and periosteal circumference (50% site), adjusted for age, height, weight and gender.

2. GWAS analysis will be performed between results of 610k illumina chip and approximately 1000 18-20 year old men from the GOOD cohort (3). Summary statistics (beta coefficients and P values) will be derived for associations with tibial cortical BMD and periosteal circumference (25% site), adjusted for age, height and weight.

3. A meta-analysis will be performed based on results from ALSPAC and GOOD, following which the top 100 hits will be identified (where necessary, missing genotypes from the 317k platform will be imputed).

4. A proportion of these hits will be carried forward for selective genotyping in the following three cohorts, using a variety of selection strategies (e.g. screening markers for evidence of cis-regulation in human osteoblast cells in collaboration with T Pastinen, McGill University):-

a. Remaining ALSPAC children not included in GWAS analysis

b. MrOS Sweden (approximately 1500 elderly men with pQCT data and available DNA)

c. Hertfordshire cohort (approximately 650 subjects (men and women combined) mean age 65 approx with pQCT data and available DNA)

5. Further meta-analyses will be performed (i) combining ALSPAC GWAS, GOOD and ALSPAC replication cohorts, and (ii) combining all five cohorts

References

1. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD 2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371(9623):1505-12.

2. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K 2008 Multiple Genetic Loci for Bone Mineral Density and Fractures. N Engl J Med.

3. Lorentzon M, Mellstrom D, Ohlsson C 2005 Association of Amount of Physical Activity With Cortical Bone Size and Trabecular Volumetric BMD in Young Adult Men:The GOOD Study. J Bone Miner res 20:1936-1943.