High-throughput technologies have opened new perspectives to unravel the genetic cause of various diseases or physiological traits, such as body mass index (BMI). Genome-wide association studies (GWAS) measure the correlation between genetic and phenotypic variation in large groups of individuals. However, the discovered genetic associations, even combined, account for only a small fraction of the BMI heritability – in part due to the complexity of obesity. Almost all previous studies assumed that the effect of all genetic variants is the same regardless of whether they are inherited from the mother or the father.
To fill this gap, in collaboration with Dr Clive Hoggart (Imperial College London) and Dr. Carlo Rivolta (University of Lausanne), we have developed a new approach for studying variants whose impact on obesity depends on their parental origin (parent-of-origin effects, POE). The results of this study, carried out at the University Institute of Social and Preventive Medicine (IUMSP) of the Lausanne Hospital (CHUV) and the Swiss Institute of Bioinformatics (SIB), were published on 31 July in the journal PLoS Genetics.
Most studies include unrelated individuals and therefore the parental origin cannot be inferred. We have discovered that, even in these samples, it is possible to detect genetic effects that are different according to their parental origin, even if the origin is unknown! This is due to the fact that at genetic markers producing these effects, one can observe an increase in the variability of BMI values among people who have inherited a different genetic code from their mother and their father (heterozygous) compared to those who have inherited the same genetic code from both parents (homozygous).
We applied this method to discover genetic markers with parent-of-origin effects (POE) on BMI. This resulted in six candidate markers showing strong POE association. We then attempted to validate the POE effect of these markers in family-based studies (where we can infer the parental origin of the variants). Two of the candidates showed a significant association in the family studies. Surprisingly, we found that the same genetic code at these markers may increase BMI when inherited from one parent, but decrease when inherited from the other.
Note: Full association summary statistics are available here.