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ASHG Presentation Highlights Sequencing-based Detection of Rare Variants Contributing to Complex Traits in Isolated Populations

SAN FRANCISCO (GenomeWeb News) – Researchers based in the Netherlands and elsewhere are relying on whole-exome sequencing in an isolated population in that country to help track down rare variants associated with complex diseases.

Speaking this morning during a session at the American Society of Human Genetics annual meeting, Erasmus Medical Center Rotterdam researcher Cornelia van Duijn explained that such sequencing approaches appear to show promise for filling in some of the heritability gaps that remain for complex traits and diseases studied by genome-wide association studies, which have tended to yield common variants with small effects.

In particular, van Duijn presented information from an effort known as the Erasmus Rucphen Family study that is being done in the Rucphen population in the southwest Netherlands. The work stems from an Erasmus-led effort known as Genetic Research in Isolated Populations, or GRIP, that has been underway since the mid-1990s.

The population being sampled for the ERF study is descended from around 150 founders who arrived in the area in 1750, van Duijn explained. Since then, individuals in the region have remained relatively isolated, but birth and baptism records have made it possible to retrace the type of pedigree information needed for family-based studies.

For the ERF project, researchers at Erasmus and their collaborators sequenced the whole exomes of 1,300 individuals from the Rucphen population, using Agilent kits to capture coding sequences that were subsequently sequenced on Illumina's HiSeq 2000 instrument.

Using this data, researchers have identified more than one million variants, including thousands of apparent premature stop mutations or missense mutations.

In the interest of gaining clues about the potential functional importance of the variants identified, van Duijn noted that they have run the variants through four different prediction algorithms to determine how many of the mutations were predicted to be damaging by at least two of the programs.

A range of phenotypes have been ascertained for the Rucphen population, ranging from clinical, biochemical, and proteomic profiling to brain and artery imaging analyses.

For their first crack at finding rare variant culprits in a complex disease, the ERF focused on major depression, drawing on endophenotype information to determine which of the study participants met the criteria for this condition.

By combining information from the Rucphen individuals who had had their exomes sequenced with data gleaned through linkage and association analyses done on around 6,000 individuals from the same population, the researchers found both common and rare variants with apparent ties to depression, van Duijn explained. In particular, results from their analyses so far point to two genes harboring common variants with ties to the condition and one gene containing a suspicious rare variant.

Going forward, the group plans to follow-up on their current findings with functional and forward genetic studies. They are also considering the possibility of whole-genome studies as a means of finding new regions and regulatory variants contributing to depression and other conditions with complex genetic underpinnings.

Speaking during the same session — which focused on the use of next-generation sequencing for studying complex trait genetics in isolated populations — the University of Miami's William Scott described studies underway in Amish populations living in Ohio and Indiana, Jeffery O'Connell from the University of Maryland spoke about research being done with Amish populations in Pennsylvania, and University of Cagliari researcher Serena Sanna outlined efforts to create an imputation resource for an isolated population on the Mediterranean island of Sardinia using low-coverage whole-genome sequencing data.

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