Population-based description of familial clustering of Chiari malformation Type I
Diana Abbott1, Douglas Brockmeyer2, Deborah W Neklason1
11Division of Genetic Epidemiology, Department of Internal Medicine, and.
Insights
Familial clustering of Chiari malformation Type I (CM-I) was investigated using a population-based genealogical resource. Results show a significant genetic contribution to CM-I predisposition, with increased risks observed in relatives.
Area of Science:
- Genetics
- Neurology
- Epidemiology
Background:
- Chiari malformation Type I (CM-I) is a neurological condition.
- Understanding the familial aggregation of CM-I is crucial for genetic counseling and research.
Purpose of the Study:
- To investigate the familial clustering of Chiari malformation Type I (CM-I).
- To determine the genetic contribution to CM-I predisposition using a population-based genealogical resource.
Main Methods:
- Utilized a population-based genealogical resource linked with medical data from Utah.
- Identified 2871 CM-I patients and analyzed relative risks (RRs) for first-, second-, and third-degree relatives.
- Employed the Genealogical Index of Familiality (GIF) test to assess pairwise relatedness among CM-I patients.
Main Results:
- Significantly increased RRs were observed for first-degree (RR 4.54) and third-degree (RR 1.36) relatives of CM-I patients.
- A significant excess of pairwise relatedness was found among CM-I patients (p < 0.001).
- Identified multiple extended pedigrees with a high prevalence of CM-I.
Conclusions:
- This study provides strong evidence for a genetic contribution to CM-I predisposition.
- Familial clustering of CM-I is significant, particularly among close relatives.
- Population-based genealogical studies are valuable for understanding the genetic basis of complex diseases.
Abstract:
OBJECTIVE A population-based genealogical resource with linked medical data was used to define the observed familial clustering of Chiari malformation Type I (CM-I). METHODS All patients with CM-I were identified from the 2 largest health care providers in Utah; those patients with linked genealogical data were used to test hypotheses regarding familial clustering. Relative risks (RRs) in first-, second-, and third-degree relatives were estimated using internal cohort-specific CM-I rates; the Genealogical Index of Familiality (GIF) test was used to test for an excess of relationships between all patients with CM-I compared with the expected distribution of relationships for matched control sets randomly selected from the resource. Pedigrees with significantly more patients with CM-I than expected (p < 0.05) based on internal rates were identified. RESULTS A total of 2871 patients with CM-I with at least 3 generations of genealogical data were identified. Significantly increased RRs were observed for first- and third-degree relatives (RR 4.54, p < 0.001, and RR 1.36, p < 0.001, respectively); the RR for second-degree relatives was elevated, but not significantly (RR 1.20, p = 0.13). Significant excess pairwise relatedness was observed among the patients with CM-I (p < 0.001), and borderline significant excess pairwise relatedness was observed when all relationships closer than first cousins were ignored (p = 0.051). Multiple extended high-risk CM-I pedigrees with closely and distantly related members were identified. CONCLUSIONS This population-based description of the familial clustering of 2871 patients with CM-I provided strong evidence for a genetic contribution to a predisposition to CM-I.
