Population genealogy resource shows evidence of familial clustering for Alzheimer disease

Cannon-Albright, Lisa; Dintelman, Sue M.; Maness, Tim; Cerny, Johni; Thomas, Alun; Backus, Steven; Farnham, James M.; Teerlink, Craig C.; Contreras, Jorge L.; Kauwe, John S. K.; Meyer, Laurence

doi:10.1212/nxg.0000000000000249

Cited by 6 publications

(8 citation statements)

References 22 publications

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“…Traditional RR estimates for AD based on comparisons of the observed to expected numbers of affected relatives of patients with AD of varying degrees based on population rates of AD death for the Utah population have been published previously, 24 and independently, based on AD diagnosis using National Veterans Health Administration hospital data. 31 Here a different approach to estimation of risk for AD has been pursued, based on specific and complete family history constellation out to TDRs for hundreds of thousands of individuals with deep genealogy and linked death certificate data. The risk estimates presented here, because they are based on specific AD family history, are much more individualized and precise risk estimates than are published elsewhere, but they are also generalized to allow risk prediction in the case of even minimal family history information.…”

Section: Discussionmentioning

confidence: 99%

Relative risk for Alzheimer disease based on complete family history

et al. 2019

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ObjectiveThe inherited component for Alzheimer disease (AD) risk has focused on close relatives; consideration of the full family history may improve accuracy and utility of risk estimates.MethodsA population resource including a genealogy of Utah pioneers from the 1800s linked to Utah death certificates was used to estimate relative risk for AD based on specific family history constellations, including from first- to third-degree relatives.ResultsAny affected first-degree relatives (FDR) significantly increased risk of AD (≥1 FDRs: relative risk [RR] 1.73, 95% confidence interval [CI] [1.59–1.87]; ≥2 FDRs: RR 3.98 [3.26–4.82]; ≥3 FDRs: RR 2.48 [1.07–4.89]; ≥4 FDRs: RR 14.77 [5.42–32.15]). Affected second-degree relatives (SDR) increased risk even in the presence of affected FDRs (FDR = 1 with SDR = 2: RR 21.29 [5.80–54.52]). AD only in third-degree relatives (TDR) also increased risk (FDR = 0, SDR = 0, TDR ≥3: RR 1.43 [1.21–1.68]). Mixed evidence was observed for differences in risk based on maternal compared to paternal inheritance; higher risks for men than women with equivalent family history, and higher risk for individuals with at least one affected FDR regardless of the relative's age at death, were observed.ConclusionsThis population-based estimation of RRs for AD based on family history ascertained from extended genealogy data indicates that inherited genetic factors have a broad influence, extending beyond immediate relatives. Providers should consider the full constellation of family history when counseling patients and families about their risk of AD.

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Section: Discussionmentioning

confidence: 99%

Relative risk for Alzheimer disease based on complete family history

et al. 2019

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“…This study used the Veteran’s Health Affairs (VHA) Genealogy/Phenotype resource, which represents a U.S. genealogy data resource that has been record-linked to nationwide medical data for the population of U.S. veterans utilizing the VHA system for medical care. This resource was created in part to allow analyses of evidence for a genetic contribution to health-related conditions (5, 6). The parent genealogy data resource extends to the early 1700s, includes individuals born in all 50 states, and currently represents approximately 71 million individuals with linked relatives, whereas the subcohort-linked VHA medical data date to the mid-1990s and include a growing total of 1.04 million VHA patients with demographic data who were record-linked to a unique individual in the genealogy data (6).…”

Section: Methodsmentioning

confidence: 99%

Evidence for an Inherited Contribution to Sepsis Susceptibility Among a Cohort of U.S. Veterans

Kempker

Martin

Rondina³

et al. 2022

Critical Care Explorations

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OBJECTIVES: Analyze a unique clinical and genealogical resource for evidence of familial clustering of sepsis to test for an inherited contribution to sepsis predisposition.DESIGN: Observational study. SETTING:Veteran's Health Affairs (VHA) Genealogy/Phenotype resource, a U.S. genealogy database with veterans individually linked to VHA electronic health records.PATIENTS: Sepsis was identified using International Classification of Disease, 9th Edition and 10th Edition codes. There were two comparison groups: one composed of the all veterans with linked data and deep genealogy and the other included 1,000 sets of controls, each set randomly sampled from the entire cohort after matching on sex and 10-year birth year range on a 1:1 ratio with cases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:There were 4,666 cases of sepsis from 2001 to 2018, of which 96% were male and 80% greater than or equal to 65 years old. Utilizing the Genealogical Index of Familiality, there was a significant excess of pairwise relatedness among sepsis cases over that in the control sets sampled from VHA population (p = 0.03). The relative risk (RR) of sepsis among identified relatives compared with the larger linked VHA cohort demonstrated an excess of sepsis cases in the first-degree (RR, 1.39; 95% CI, 1.03-1.92; p = 0.05) and second-degree (RR, 1.50; 95% CI, 1.07-2.17; p = 0.04) relatives that were not demonstrated in higher degree relatives. The sepsis cases clustered into 1,876 pedigrees of which 628 had a significant excess of sepsis cases among the descendants (p < 0.05). CONCLUSIONS:The data from this cohort of nearly all male U.S. veterans demonstrate evidence for contribution of an inherited predisposition to sepsis and the existence of pedigrees with a significant excess of diagnoses that provide a valuable resource for identification of the predisposition genes and variants responsible. This complements studies on individual genetic variants toward estimating the heritability patterns and clinical relevance of genetic sepsis predisposition.

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“…The linked diagnosis codes date to the mid-1990s and include a total of 110 million ICD-9 and 26 million ICD-10 records for the 1 million linked patients. The VHA resource was created to analyze evidence for a genetic contribution to health-related conditions (16,17). Of the VHA patients with linked data, 273,227 have genealogy data including at least both parents, all four grandparents, and at least two of eight great-grandparents.…”

Section: Veterans Health Administration Datamentioning

confidence: 99%

“…The Veterans Health Administration (VHA) Genealogy Resource represents a genealogy of the United States that has been record-linked to nationwide phenotype data for U.S. veterans (16,17). The partial U.S. genealogy currently represents 70 million individuals with linked relatives extending to the early 1700s, including individuals born in all 50 states (16,17). Just over 1 million of the approximately 13 million unique patients with demographic data in the VHA system were record-linked to a unique individual in the genealogy.…”

Section: Veterans Health Administration Datamentioning

confidence: 99%

“…The Genealogical Index of Familiality (GIF) method was used to test for excess relatedness among individuals diagnosed with unilateral VS. This test was originally designed for use with the UPDB and has also been used on the VHA resource (15)(16)(17)(18). The GIF test compares the average pairwise relatedness of all pairs of VS cases with the expected pairwise relatedness of a set of matched/linked control individuals from the UDPB (or VHA) population.…”

Section: Genealogical Index Of Familialitymentioning

confidence: 99%

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Is There an Inherited Contribution to Risk for Sporadic Unilateral Vestibular Schwannoma? Evidence of Familial Clustering

et al. 2022

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Object: Unlike the autosomal dominant inheritance of neurofibromatosis 2, there are no known inherited risk factors for sporadic, unilateral vestibular schwannoma (VS), which comprise most VS cases. The authors tested a hypothesis positing a genetic contribution to predisposition to these lesions by analyzing familial clustering of cases. Methods: Familial clustering of individuals with unilateral VS was analyzed in two independent genealogical resources with linked diagnosis data: the Veterans Health Administration Genealogy Resource and the Utah Population Database. Tests for excess relatedness, estimation of relative risks (RRs) in close and distant relatives, and identification of pedigrees with a significant excess of unilateral VS among descendants were performed. Results: The average pairwise relatedness of the Veterans Health Administration Genealogy Resource VS cases significantly exceeded the expected relatedness ( p = 0.016), even when close relationships were ignored ( p = 0.002). RR for third-and fifth-degree relatives developing VS were significantly elevated (RR, 60.83; p = 0.0005; 95% confidence interval [CI], 7.37-219.73) and (RR, 11.88; p = 0.013; 95% CI, 1.44-42.90), respectively. No VS-affected first-, second-, or fourth-degree relatives were observed. In the Utah Population Database population, no first-or second-degree relatives with VS were observed. RR for fifth-degree relatives developing VS was significantly elevated (RR, 2.23; p = 0.009; 95% CI, 1.15-3.90). Conclusion: These results provide strong evidence for an inherited predisposition to sporadic, unilateral VS. This study exhibits the value of genealogical resources with linked medical data for examining hypotheses regarding inherited predisposition. The high-risk unilateral VS pedigrees identified in two independent resources provide a powerful means of pursuing predisposition gene identification.

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Population genealogy resource shows evidence of familial clustering for Alzheimer disease

Cited by 6 publications

References 22 publications

Relative risk for Alzheimer disease based on complete family history

Relative risk for Alzheimer disease based on complete family history

Evidence for an Inherited Contribution to Sepsis Susceptibility Among a Cohort of U.S. Veterans

Is There an Inherited Contribution to Risk for Sporadic Unilateral Vestibular Schwannoma? Evidence of Familial Clustering

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