Contributions of rare and common variation to early-onset and atypical dementia risk.
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ABSTRACT:
SUBMITTER: Wright CA
PROVIDER: S-EPMC10393188 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
Publications
Contributions of rare and common variation to early-onset and atypical dementia risk.
Wright Carter A CA Taylor Jared W JW Cochran Meagan M Lawlor James M J JMJ Moyers Belle A BA Amaral Michelle D MD Bonnstetter Zachary T ZT Carter Princess P Solomon Veronika V Myers Richard M RM Love Marissa Natelson MN Geldmacher David S DS Cooper Sara J SJ Roberson Erik D ED Cochran J Nicholas JN
Cold Spring Harbor molecular case studies 20230601 3
We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with 68 newly described in this report. Of those 68, 62 patients self-reported white, non-Hispanic ethnicity and 6 reported as African-American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria fo ...[more]
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Project description:We collected and analyzed genomic sequencing data from individuals with clinician- diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six reported as African American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non- APOE polygenic risk scores than patients with late onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.
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Project description:ImportanceAtrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.ObjectiveTo identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).Design, setting, and participantsThis was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF.ExposuresRare pLOF variants and an AF PRS.Main outcomes and measuresRisk of AF and incident HF or CM prior to and subsequent to AF diagnosis.ResultsA total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).Conclusions and relevanceRare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.
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Project description:Early onset drusen maculopathy (EODM) can lead to advanced macular degeneration at a young age, affecting quality of life. However, the genetic causes of EODM are not well studied. We performed whole genome sequencing in 49 EODM patients. Common genetic variants were analysed by calculating genetic risk scores based on 52 age-related macular generation (AMD)-associated variants, and we analysed rare variants in candidate genes to identify potential deleterious variants that might contribute to EODM development. We demonstrate that the 52 AMD-associated variants contributed to EODM, especially variants located in the complement pathway. Furthermore, we identified 26 rare genetic variants predicted to be pathogenic based on in silico prediction tools or based on reported pathogenicity in literature. These variants are located predominantly in the complement and lipid metabolism pathways. Last, evaluation of 18 genes causing inherited retinal dystrophies that can mimic AMD characteristics, revealed 11 potential deleterious variants in eight EODM patients. However, phenotypic characteristics did not point towards a retinal dystrophy in these patients. In conclusion, this study reports new insights into rare variants that are potentially involved in EODM development, and which are relevant for future studies unravelling the aetiology of EODM.
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Project description:ObjectiveTo evaluate the association of early-adulthood and mid-adulthood hypertension with dementia in men and women.MethodsWe evaluated 5,646 members of a diverse integrated health care delivery system who had clinical examinations and health survey data from 1964 to 1973 (mean age 32.7 years; early adulthood) and 1978-1985 (mean age 44.3 years; mid-adulthood) and were members as of January 1, 1996 (mean age 59.8 years). Hypertension categories based on measurements of blood pressure (BP) and change in hypertension categories between the 2 examinations (e.g., onset hypertension) were used to predict dementia incidence from January 1, 1996, to September 30, 2015. Cox proportional hazard models were adjusted for demographics, vascular comorbidities, and hypertension treatment; inverse probability weighting accounted for differential attrition between first BP measurement and start of follow-up.ResultsA total of 532 individuals (9.4%) were diagnosed with dementia. Early adulthood hypertension was not associated with dementia, though effect estimates were elevated among women. Mid-adulthood hypertension was associated with 65% (95% confidence interval [CI] 1.25-2.18) increased dementia risk among women but not men. Onset of hypertension in mid-adulthood predicted 73% higher dementia risk in women (95% CI 1.24-2.40) compared to stable normotensive. There was no evidence that hypertension or changes in hypertension increased dementia risk among men.ConclusionsThough midlife hypertension was more common in men, it was only associated with dementia risk in women. Sex differences in the timing of dementia risk factors have important implications for brain health and hypertension management.
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Project description:ObjectiveBoth rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions.MethodGenetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psychiatric Genomics Consortium were examined. Three classes of rare CNVs were assessed: CNVs previously associated with schizophrenia, CNVs with large deletions ≥500 kb, and total CNV burden. The mean polygenic risk scores (PRSs) between study subjects with and without rare CNVs were compared, and joint effects of PRS and CNVs on schizophrenia liability were modeled by using logistic regression.ResultsSchizophrenia case subjects carrying risk CNVs had a lower polygenic risk than case subjects without risk CNVs but a higher risk than control subjects. For case subjects carrying known risk CNVs, the PRS was diminished in proportion to the effect size of the CNV. The strongly associated 22q11.2 deletion required little added PRS to produce schizophrenia. Large deletions and increased CNV burden were also associated with lower polygenic risk in schizophrenia case subjects but not in control subjects or after removal of known risk CNV carriers.ConclusionsThe authors found evidence for interactive effects of PRS and previously associated CNVs for risk for schizophrenia, and the results for large deletions and total CNV burden support an additive model. These findings offer insights into the genetic architecture of schizophrenia by illuminating how different established genetic risk factors act and interact to influence liability to schizophrenia.
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Project description:We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41-76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in APP, C9orf72, CSF1R, and MAPT Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2-5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2 All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE ε4 alleles. One patient had two APOE ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.
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