Ok, so, suppose that pretty much everyone who grew up in Britain in the 1960s has 100 identifiable genetic variants that pretty much no one else has, and by coincidence there were some schools in Britain in the 1960s that taught a bunch of awful dietary habits to schoolchildren, and so there’s a major correlation between those variants and developing diabetes. It also happens that 10 of those variants actually make the body more susceptible to diabetes, and 10 of them protect against diabetes, and the rest have zero causal effect. @GeneSmith , what would the GWAS conclude in this case, and how common and important are cases like it? (E.g. I would guess there are a bunch of genes that correlate with socioeconomic status but aren’t causal.)
This is where sibling validation becomes very useful: if the observed effect is due an actual direct genetic effect, it will allow you to distinguish siblings with higher and lower diabetes risk. If it’s due to some weird environmental gene correlation, it won’t.
If you did the sibling testing you would find that 10 of the associated genes replicated and 90 did not.
It seems implausible that everyone who grew up in Britain in the 1960s would have genetic variants that no one else has. Their parents and children would have grown up in different decades, whether in Britain or elsewhere, and they would also have those variants.
Ok, so, suppose that pretty much everyone who grew up in Britain in the 1960s has 100 identifiable genetic variants that pretty much no one else has, and by coincidence there were some schools in Britain in the 1960s that taught a bunch of awful dietary habits to schoolchildren, and so there’s a major correlation between those variants and developing diabetes. It also happens that 10 of those variants actually make the body more susceptible to diabetes, and 10 of them protect against diabetes, and the rest have zero causal effect. @GeneSmith , what would the GWAS conclude in this case, and how common and important are cases like it? (E.g. I would guess there are a bunch of genes that correlate with socioeconomic status but aren’t causal.)
This is where sibling validation becomes very useful: if the observed effect is due an actual direct genetic effect, it will allow you to distinguish siblings with higher and lower diabetes risk. If it’s due to some weird environmental gene correlation, it won’t.
If you did the sibling testing you would find that 10 of the associated genes replicated and 90 did not.
It seems implausible that everyone who grew up in Britain in the 1960s would have genetic variants that no one else has. Their parents and children would have grown up in different decades, whether in Britain or elsewhere, and they would also have those variants.