The Dr. Wayne Gulliver Project
This paper describes a genetic linkage study conducted in Newfoundland, Canada, aimed at identifying a potential susceptibility gene for psoriasis. The study leverages the unique genetic characteristics of the Newfoundland population – a relatively isolated group with a limited founder effect – to increase the power of detecting genetic links. Here's a detailed breakdown:
Background: Psoriasis is a common inflammatory skin disease with a strong genetic component. At the time of this study (1999), the specific genes responsible for psoriasis susceptibility were largely unknown. Family studies had established a genetic predisposition, but pinpointing the genes was challenging due to the complex inheritance patterns.
Study Design: The researchers conducted a genome-wide linkage analysis in 23 Newfoundland families, each containing at least two individuals affected by psoriasis. Linkage analysis looks for regions of the genome that are inherited along with the disease more often than expected by chance. This suggests a gene in that region is linked to psoriasis.
Population: The Newfoundland population was chosen due to its history of relative isolation. This isolation resulted in a limited number of founding families contributing to the gene pool, leading to reduced genetic diversity and increased linkage disequilibrium (meaning genes close together on a chromosome are more likely to be inherited together). This makes it easier to detect genetic linkages.
Methods: DNA was extracted from family members. Researchers used polymorphic markers (specifically, microsatellite markers) distributed across the entire genome to track inheritance patterns. Statistical analysis (lod score calculation) was used to determine if the co-inheritance of psoriasis and specific markers was statistically significant. A lod score of 3 or higher is generally considered evidence of linkage.
Results: The study found suggestive evidence of linkage to chromosome 17q, specifically in the region 17q25. The highest lod score achieved was 2.17, falling short of the conventional threshold for definitive linkage (lod score of 3). However, the authors noted that the study was underpowered due to the relatively small sample size.
Conclusion: The authors concluded that chromosome 17q25 represents a region of potential interest for psoriasis susceptibility. They recommended further investigation with larger sample sizes and denser marker coverage to confirm the linkage and identify the causative gene(s).
A. Significance & Context (1999):
Early Genetic Exploration: This study was significant because it was one of the early attempts to use modern genetic techniques (genome-wide linkage analysis) to unravel the genetic basis of psoriasis. Prior to this, research relied heavily on family studies and twin studies, which provided evidence of heritability but lacked the precision to identify specific genes.
Newfoundland's Value: The choice of the Newfoundland population was a clever strategy. The founder effect and limited genetic diversity increased the statistical power to detect linkage, making it a valuable population for genetic studies of complex diseases.
Pre-PSORS1 Era: Importantly, this study predated the identification of PSORS1 (Psoriasis Susceptibility 1), the first major psoriasis susceptibility gene, located on chromosome 6p21.3. PSORS1 encodes for IL-23R, a key player in the immune pathways driving psoriasis. The 17q finding, while not definitive, opened up the possibility of other susceptibility genes beyond the initial one.
B. Why the Lod Score Wasn't Definitive:
Sample Size: The primary limitation of the study was its relatively small sample size (23 families). Linkage studies require a substantial number of affected individuals and family members to achieve sufficient statistical power.
Marker Density: The density of microsatellite markers used was limited by the technology available in 1999. A denser map of markers would have increased the resolution and potentially revealed a stronger linkage signal.
Genetic Heterogeneity: Psoriasis is a genetically heterogeneous disease, meaning multiple genes can contribute to its development. The 17q region might be involved in a subset of psoriasis cases, and the signal could be diluted by the presence of other genetic factors.
Phenotypic Variability: Variations in the clinical presentation of psoriasis (severity, type, age of onset) could also contribute to the complexity and make it harder to detect a clear genetic link.
C. What Happened After This Study? (Post-1999 Developments)
PSORS1 Discovery: The discovery of PSORS1 in 2000 revolutionized psoriasis genetics. It became clear that this gene accounted for a significant proportion of psoriasis susceptibility, particularly in individuals of European ancestry.
Further Genome-Wide Association Studies (GWAS): With the advent of high-throughput genotyping technologies, GWAS became the dominant approach to identifying psoriasis susceptibility genes. GWAS scan the entire genome for common genetic variants (single nucleotide polymorphisms or SNPs) that are associated with the disease.
Confirmation of Other Loci: GWAS have identified numerous other psoriasis susceptibility loci, including IL23A, IL17A, TNFAIP3, ERAP1, and many others. These genes are involved in various aspects of immune regulation and inflammation.
Revisiting 17q: While the 17q region identified in the Newfoundland study hasn't received as much attention as other loci, subsequent research has explored it further. Some studies have suggested potential involvement of genes in the 17q25 region in immune function and inflammation, but a definitive causative gene hasn't been identified. It's possible that the initial signal was a false positive, or that the effect of genes in this region is subtle and requires larger studies to detect.
D. Overall Assessment:
The Newfoundland Study was a valuable early contribution to the field of psoriasis genetics. While it didn't definitively identify a psoriasis susceptibility gene, it highlighted the potential of linkage analysis and the usefulness of isolated populations for genetic research. The study paved the way for more sophisticated genetic studies that ultimately led to the identification of numerous genes involved in psoriasis pathogenesis. It serves as a reminder of the iterative nature of scientific discovery – early studies often provide clues and directions for future research.
You can find the full text of the article here: https://pubmed.ncbi.nlm.nih.gov/10582157/