One of the mainobjectives ofourprojectisto evaluate the contribution of polar overdominance-like effects to inherited predisposition to common complex diseases in human.

Details of this part of our project is as follows:

Genome-wide association studies (GWAS) have uncovered tens of loci influencing nearly all studied common complex diseases, and this has lead to essential new insights in disease pathogenesis. However, the identified risk loci typically explain <= 20% of inherited predisposition, raising the so-called "missing heritability issue". Understanding the missing heritability is viewed one of the most important objectives of modern medical genetics. Several hypotheses have been formulated to account for the missing heritability and are presently being evaluated. These include the quasi-infinitesimal architecture of complex traits and the role of rare, highly penetrant genetic variants, to name just the most publicized ones.

One alternative explanation is the contribution of non-Mendelian modes of inheritance, including parent-of-origin effects. While studying a muscular hypertrophy of sheep, known as the callipyge phenotype, we discovered one such completely novel non-Mendelian inheritance pattern, referred to as polar overdominance: only heterozygous animals inheriting the CLPG mutation from their father express the phenotype. Recent studies conducted in human, mice and domestic animals indicate that polar overdominance-like effects may be more common than initially suspected.

We are in the process if submitting a grant to the ERC, referred to as the SOLID GOLD project. The objectives of the Solid Gold project are (i) to use state-of-the-art genomic approaches to achieve a comprehensive understanding of the molecular mechanisms underlying polar overdominance at the ovine callipyge locus, and (ii) to evaluate the contribution of polar overdominance-like effects to inherited predisposition to common complex diseases in human.

We are requesting access to the ALSPAC data in the context of the second objective. Indeed, (i) having genotype mother-child duos will allow determination of the parental origin of the marker alleles inherited by the child, which is needed to test for parent-of-origin effects including polar overdominance, (ii) the exceptional size of the ALSPAC cohort provides excellent detection power, and (iii) the broad spectrum of recorded phenotypes increases the probability of detection of positive results.