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.

GRIP study
In 1995 we have started together with Van Duijn (Dept of Epidemiology & Biostatistics, ErasmusMC) our research program “Genetic Research in Isolated Populations” (GRIP). This population is a recent genetic isolate in the southwestern Netherlands.5 Briefly, this population was founded in the middle of the 18th century by approximately 150 individuals and was isolated until the last few decades. Characterized by rapid growth and minimal immigration, the isolate now includes approximately 20,000 inhabitants.
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 Alzheimer disease (see figure below).For Parkinson’s disease, a disorder with a relatively low heritability, we have been able to identify a disease gene DJ-1 in GRIP.

ERF study
Within the GRIP population we have started the ERF (Erasmus Rucphen Family) study.  Twenty couples living in the region in the 19th century were chosen. These couples parented a minimum of 6 children, each of whom was baptized in the latter half of the nineteenth century in the community church. All living descendants of these pairs (as well as their spouses), ascertained on the basis of municipal and baptismal records, were traced and invited to participate (n  3,000). This population exhibits reduced genetic heterogeneity and increased linkage disequilibrium, compared to general populations.

Figure 1. The entire pedigree with 4,645 members, including 103 patients with late-onset AD, from the GRIP population. Men are represented with squares and women with circles. Black dots represent marriage nodes. Affected individuals are represented in black. Unknown affection status is represented with yellow. For simplicity, unaffected relatives of the patients are not shown. This figure was drawn using Pedfiddler version 0.5.