After obtaining his first doctorate in 1999, Igor Rudan started to develop the biobank called "10,001 Dalmatians". At the time, this was a very rare DNA-based human biobank in a middle-income country. This resource for genetic epidemiological studies was established in a series of genetic isolate islands off the coast of
Dalmatia region in Croatia. In 2001 he received the International Research Development Award from the
Wellcome Trust for his research and vision. Further development of this biobank was achieved through collaboration with Professors Harry Campbell from the
University of Edinburgh and Alan F. Wright from the Human Genetics Unit of the
Medical Research Council (MRC) in Edinburgh.
The outbreeding theory: Studying the effects of human inbreeding and admixture Rudan's early work focused on studying the effects of inbreeding and admixture on
human health and
disease. At the time, in the early 2000s, one of the central questions relevant to
gene mapping was to predict the genetic architecture of complex quantitative biological traits that underlie common late-onset diseases. Most research of that period assumed that it was "oligogenic", i.e., that only a handful of genes would confer the majority of genetic risk for complex quantitative traits and diseases. Using inbreeding studies within his PhD research, Rudan and his colleagues showed that the genetic architecture of those traits must be highly polygenic, with at least several hundred loci contributing to the genetic risk of human hypertension and late-onset diseases. These studies, published in 2003, were regarded as controversial at the time, which made them difficult to publish. Their implications were summarized in a review published by the influential scientific journal
Trends in Genetics in 2003. A decade later, hundreds of
genome-wide association studies have shown that the
genetic architecture of human
quantitative traits and common complex
disease of late-onset is highly
polygenic. Rudan's work on studying the effects of
inbreeding and admixture on human disease was continued at the
University of Edinburgh through the PhD theses by Ozren Polasek, Ruth McQuillan, and Peter Joshi. After 16 years of continuous research, it resulted in a paper in
Nature, demonstrating effects on stature and cognition in diverse human populations. Based on these results, Rudan proposed "the
outbreeding theory", i.e., that large human movements, migrations and urbanization may be partly driving, through so-called "
hybrid vigor", the observed secular trends, improvements in public
health indicators and
human lifespan.
10001 Dalmatians: Genome-wide association studies of quantitative traits Rudan developed the resource "10001 Dalmatians" with the help of his close collaborators Harry Campbell and Ozren Polašek. The biobank mainly comprised the examinees from the islands of Vis and Korčula in Dalmatia, Croatia. With the advent of "chips" for genome-wide scans developed by the company
Illumina, genome-wide association studies became possible and the Croatian resource was among the first to carry them out. However, due to the highly polygenic nature of the studied traits, gene discovery required very large sample sizes. This led to many European and global biobanks joining together to form large collaborative consortia. Their work led to hundreds of original research papers, many of which were published in the leading science journals -
Nature,
Science or
Nature Genetics. In collaboration with other international biobanks, the "10001 Dalmatians" resource contributed to the discovery of several thousands of human genetic variants that were associated with quantitative biological traits and complex diseases. Igor Rudan co-led the discovery of the
SLC2A9 gene variants that were associated with uric acid levels and gout disease. In collaboration with Professor Gordan Lauc from the University of Zagreb, he also co-led the first two studies that identified genetic variants associated with human N-glycans levels. == Career in global health ==