Comparative assessment of different familial aggregation methods in the context of large and unstructured pedigrees

Weichenberger, Christian X.; Rainer, Johannes Michael; Pattaro, Cristian; Pramstaller, Peter P.; Domingues, Francisco S.

doi:10.1093/bioinformatics/bty541

Cited by 3 publications

(2 citation statements)

References 26 publications

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“…Analogously, 10,399 unaffected participants served as controls, and after removal of 807 singletons and 23 opt-outs from analysis in the control group, we arrived at 9569 controls and 103 cases, connected by 9898 un-phenotyped individuals. As discussed previously [ 21 ], in the context of large pedigrees, FamAgg’s Kinship Sum test represents the best method to detect familial aggregation as this test can quantitatively identify individuals with a significantly high number of affected kin pedigree members. Briefly, for a given case, this test takes the sum of kinship coefficients over all affected relatives and computes an empirical p -value derived from a background distribution resulting from 1,000,000 rounds of randomly assigning the 103 cases in the same set of pedigrees.…”

Section: Methodsmentioning

confidence: 99%

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

et al. 2021

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Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.

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Section: Methodsmentioning

confidence: 99%

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

et al. 2021

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“…Index test in this work). For an in-depth assessment of these tests, refer to [ 25 ]. Each test returns an empirical p -value to observe an outcome at least as extreme as the one found in this study.…”

Section: Methodsmentioning

confidence: 99%

Familial Aggregation of Endemic Congenital Hypothyroidism Syndrome in Congo (DR): Historical Data

Weichenberger¹,

Rivera

Vanderpas

2020

Nutrients

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Familial aggregation of endemic congenital hypothyroidism (CH) in an iodine-deficient population from northern Congo (Democratic Republic (DR)) was analysed on data collected four decades ago (1979–1980). During a systematic survey of 62 families, 46 endemic CH subjects (44 myxedematous and 2 neurological) were identified based on clinical evidence within a village cohort of 468 subjects. A distribution analysis showed that two families presented significant excess of cases versus a random background distribution. Both families were characterised by two healthy parents having all of their five offspring affected by some form of endemic CH. Goitre prevalence in endemic CH was lower than that in the general population, while goitre prevalence in the unaffected part of the cohort (parents and siblings) was similar to that of the general population. Some unidentified genetic/epigenetic factor(s) could contribute to the evolution of some iodine-deficient hypothyroid neonates through irreversible and progressive loss of thyroid functional capacity during early childhood (<5 years old). Besides severe iodine deficiency, environmental exposure to thiocyanate overload and selenium deficiency, factors not randomly distributed within families and population, intervened in the full expression of endemic CH. Further exploration in the field will remain open, as iodine deficiency in Congo (DR) was eliminated in the 1990s.

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Diverticulitis Familiality: A Statewide Case-Control Study

Horns

Ramsay

Huang

et al. 2023

Journal of the American College of Surgeons

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Background: The etiology of diverticulitis is multifactorial and poorly understood. We estimated the familiality of diverticulitis using the Utah Population Database (UPDB), a statewide database linking medical records with genealogy data. Study Design: We identified patients with diverticulitis diagnosed between 1998-2018 and age- and sex-matched controls in the UPDB. Risk of diverticulitis in family members of cases and controls was calculated using multivariable Poisson models. We performed exploratory analyses to determine the association of familial diverticulitis with severity of disease and age of onset. Results: The study population included 9,563 diverticulitis cases (with 229,647 relatives) and 10,588 controls (with 265,693 relatives). Relatives of cases were more likely to develop diverticulitis (incidence rate ratio (IRR) 1.5, 95%CI 1.4,1.6) compared with relatives of controls. Further, there was an elevated risk of diverticulitis among first-degree (IRR 2.6, 95% CI 2.3,3.0), second-degree (IRR 1.5, 95%CI 1.3,1.6), and third-degree relatives of cases (IRR 1.3, 95%CI 1.2,1.4). Complicated diverticulitis was more common among relatives of cases compared with relatives of controls (IRR 1.6, 95%CI 1.4,1.8). Age at diverticulitis diagnosis was similar between groups (relatives of cases 0.2 years older than relatives of controls, 95%CI -0.5,0.9). Conclusion: Our results indicate that the first-, second-, and third-degree relatives of diverticulitis patients are at elevated risk of developing diverticulitis. This information may aid surgeons in counseling patients and family members about diverticulitis risk and can inform the development of future risk-stratification tools. Further work is needed to clarify the causal role and relative contribution of various genetic, lifestyle, and environmental factors in the development of diverticulitis.

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Comparative assessment of different familial aggregation methods in the context of large and unstructured pedigrees

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 3 publications

References 26 publications

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

Familial Aggregation of Endemic Congenital Hypothyroidism Syndrome in Congo (DR): Historical Data

Diverticulitis Familiality: A Statewide Case-Control Study

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