Search for genes involved in complex disorders

Ben A Oostra

Genetic factors play an important role in the etiology of various complex genetic disorders. Remarkably little progress has been made in the identification of genetic components underlying frequent neurologic and neuropsychiatric diseases. It is becoming increasingly clear that these disorders are genetically complex and may often result from an interplay of genetic and environmental risk factors. Since the number of extended families in which multiple patients that are alive are often rare, the use of classical linkage analysis is of limited value in studies of the molecular genetics of these disorders. To unravel the genetics of complex disorders requires a different strategy which is capable of detecting effects of genetic factors which may depend strongly on the presence of other genetic and/or environmental risk factors. The situation is more favourable in relatively isolated populations.

In 1995 we have started together with Van Duijn (Dept of Epidemiology, ErasmusMC) our research program “Genetic Research in Isolated Populations” (GRIP). This programme is conducted in a genetically isolated population in the Southwest of the Netherlands. As part of the GRIP programme, we have studied several complex genetic disorders including diabetes mellitus type 1 and 2, Parkinson’s disease, Alzheimer’s disease, ADHD, and Multiple Sclerosis Using municipal records and genealogical data bases of this isolated population of 20,000 residents, we were able to link most of the patients of each disorder to a common ancestor. An example is shown for Diabetes type I (see figure below).For two disorders, diabetes type I and type II, we have successfully finished the genome screen while the analyses in Alzheimer patients and Parkinson patients are still ongoing. For diabetes type I and II we were able to localise a region. This region was associated with increased fasting glucose levels in first degree relatives, suggesting this segment harbours most likely a gene involved in the pathogenesis of diabetes in the GRIP population. For Parkinson’s disease, a disorder with a relatively low heritability, we have been able to identify a disease gene DJ-1 in GRIP.

Recent publication:

Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism
Science, Vol. 299, Issue 5604, 256-259, January 10, 2003