DNA from related UK Biobank participants has revealed how versions of some genes affect us differently depending on which parent we inherit them from.
Summary
An analysis of 100,000 UK Biobank participants’ DNA has revealed how versions of some genes have opposite effects depending on which parent we inherit them from. One example is a gene that affects the likelihood of developing type 2 diabetes: inheriting a version of this gene from the mother reduces diabetes risk by 9%, while inheriting it from the father increases risk by 14%. Accounting for these ‘parent-of-origin’ effects could make for better polygenic risk scores.
Researchers discovered 30 cases in which versions of a gene have different – sometimes opposite – effects depending on which parent they came from. One example is a gene that affects the likelihood of developing type 2 diabetes: inheriting a version of this gene from the mother reduces diabetes risk, while inheriting it from the father increases risk.
The team analysed DNA from more than 100,000 relatives among UK Biobank participants, making it the largest systematic search for these ‘parent-of-origin’ effects. Understanding the effect better could make for more accurate polygenic risk scores, which calculate how our genetic makeup affects our health.
The origin of parent-of-origin effects
One of the most intriguing results is the large proportion of parent-of-origin effects that pull traits in opposite directions.
Dr Robin Hofmeister, University of Lausanne, Switzerland
We usually have two copies (called alleles) of all our genes – one from each parent. Each parent can pass on a slightly different version (aka variant) of each gene.
For 99% of our genes, it doesn’t matter which parent we inherited a variant from; the outcome will be the same. The remaining 1% of genes show parent-of-origin effects: the same variant has a different effect depending on which parent it originated from.
Scientists have now found 30 cases of parent-of-origin effects, some new and some already known. Many affect genes related to the body’s energy regulation and growth, which could reflect the phenomenon’s origin: an evolutionary conflict between paternal and maternal genes.
Pulled in opposite directions
The analysis included DNA from 100,000 UK Biobank participants with a sibling, cousin or other relative who’s also a participants
A father’s genes might promote his offspring’s growth and therefore survival. But because this comes at the cost of the mother’s resources, her genes might limit growth to ensure she can raise further children.
“One of the most intriguing results is the large proportion of parent-of-origin effects that we refer to as ‘bipolar’ effects… they pull traits in opposite directions,” says Robin Hofmeister, one of the study’s leaders from the University of Lausanne in Switzerland. “Before this, it was mostly assumed that we will have one parental allele with no effect at all and the other parental allele with an effect.”
For example, inheriting one variant from the father increases diabetes risk by 14%. Inheriting the exact same variant from the mother reduces this risk by 9%. “Accounting for the inheritance origin of the alleles could make polygenic risk scores a bit more accurate,” adds Hofmeister’s colleague and study co-leader Zoltán Kutalik.
Related participants
Accounting for the inheritance origin of the alleles could make polygenic risk scores a bit more accurate.
Dr Zoltán Kutalik, University of Lausanne, Switzerland
Parent-of-origin effects are subtle and hard to find. Until now, researchers had to compare genetic data from parents and children. But “parental genomic information is not available in most biobanks – even in UK Biobank, you have only 5,000 individuals for which you have a [parent’s DNA, because they’re both participants],” Kutalik says.
Kutalik and his team developed a completely new way to reveal parent-of-origin effects: they deduced the parental origin of genes by comparing DNA from siblings, cousins and cousins-once-removed.
“The finding that there’s a parent-of-origin effect is not particularly novel, but the way they’ve gone about it really does set up a method so that we can use these biobanks for further discovery,” geneticist Michael Gabbett from the Queensland University of Technology, Australia, told Nature.
