Forskningsartikler

Background: Genome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology. Methods: Here, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB. Findings: Between November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported at GBA, SNCA, STX1B, and APOE. However, the sex-stratified analysis revealed that the GBA and SNCA signals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far. Interpretation: These data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.

Elizabeth Gibbons, Arvid Rongve, Itziar de Rojas, Alexey Shadrin, Kaitlyn Westra, Allison Baumgartner, Levi Rosendall, Zachary Madaj, Dena G. Hernandez, Owen A. Ross, Valentina Escott-Price, Claire Shepherd, Laura Parkkinen, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge,…Geir Selbæk…Jose Bras

Background:
Nursing home (NH) residents are in their last phase of life, and two aims of the NH’s medical care in Norway is to prevent unnecessary hospital admissions that would not benefit the resident and to facilitate a peaceful death in familiar surroundings when the time comes. However, little is known about the share of residents dying in NHs and the causes of death. We therefore evaluated the cause and place of death in a cohort of NH residents followed from the time of NH admission until death.

Methods:
NH residents were followed from admission to the NH and over the entire course of their NH stay. Demographic and clinical data were collected. Cause and place of death were retrieved from the Norwegian Cause of Death Registry.

Results:
Of 1283 residents, 6.2% died in hospital and 91.2% in a NH. Those who died in hospitals were more often male, died sooner after NH admission, had a less severe degree of dementia and had poorer general health. Dementia was the most common underlying cause of death, followed by cardiovascular disease.

Conclusions:
Dementia is one of the main causes of death in NH residents. In addition, our findings indicate a low number of inappropriate referrals to hospital during the last stage of life. However, further research should explore whether the terminal phase of NH residents is formed in accordance with their preferences and whether appropriate palliative care is offered.

Corinna Vossius, Sverre Bergh, Geir Selbæk, Bjørn Lichtwarck and Janne Myhre