Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10-7). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.

The T-type voltage-gated calcium channel CaV3.3 is expressed in GABAergic neurons of the thalamic reticular nucleus (TRN), where its pacemaking activity controls sleep spindle rhythmogenesis during the non-rapid eye movement (NREM) phase of natural sleep. Previously, we established CACNA1I, the gene coding for CaV3.3, as a disease gene for neurodevelopmental disease with or without epilepsy. Here we report three newly identified activation-gate-modifying heterozygous missense variants of CACNA1I, found in four unrelated patients with neurodevelopmental disease with or without seizures. One of these variants, p.(Met1425Val), is an amino-acid substitution at the same position as previously published variant p.(Met1425Ile). Notably, the other two variants studied here are also a pair of two different substitutions of the same amino acid: p.(Ala398Val) and p.(Ala398Glu). By using site-directed mutagenesis, voltage-clamp electrophysiology, computational modelling of neuronal excitability, and structure modelling, we found that the two substitutions of M1425 both result in a gain of channel function including left-shifted voltage-dependence of activation and inactivation, slowed inactivation and deactivation kinetics, and increased neuronal excitability. Remarkably, the two substitutions of A398 show opposite effects on channel function. While substitution A398E leads to a gain of channel function, A398V results in decreased current density, accelerated gating kinetics, and a decreased neuronal excitability. The lack of seizures in the two independent p.(Ala398Val) patients correlates with the absence of increased neuronal excitability in this variant. This is the first report of a gate-modifying CaV3.3 channel variant with partial loss-of-function effects associated with developmental delay and intellectual disability without seizures. Our study corroborates the role of CaV3.3 dysfunction in the etiology of neurodevelopmental disorders. Moreover, our data suggest that substantial gain-of-function of CaV3.3 leads to the development of seizures, whereas both gain- and loss-of-function variants of CACNA1I can cause neurodevelopmental disease.

BACKGROUND:Although compassion is a crucial element of physicians' professional performance and high-quality care, research shows it often remains an unmet need of patients. Understanding patients' and physicians' perspectives on compassionate care may provide insights that can be used to foster physicians' ability to respond to patients' compassion needs. Therefore, this study aims to understand how both patients and physicians experience the concept and practice of compassionate care. METHODS:We conducted semi-structured interviews with eight patients and ten resident physicians at a University Medical Center in the Netherlands. Using thematic analysis, we separately coded patient and resident transcripts to identify themes capturing their experiences of compassionate care. This study was part of a larger project to develop an educational intervention to improve compassion in residents. RESULTS:For both patients and residents, we identified four themes encompassing compassionate care: being there, empathizing, actions to relieve patients' suffering, and connection. For residents, a fifth theme was professional fulfillment (resulting from compassionate care). Although patients and residents both emphasized the importance of compassionate care, patients did not always perceive the physician-patient encounter as compassionate. According to residents, high workloads and time pressures hindered their ability to provide compassionate care. DISCUSSION AND CONCLUSION:Patients and residents have similar and varying understandings of compassionate care at the same time. Understanding these differences can aid compassion in medical practice. Based on the findings, three topics are suggested to improve compassion in residents: (1) train residents how to ask for patients' compassion needs, (2) address residents' limiting beliefs about the concept and practice of compassion, and (3) acknowledge the art and science of medicine cannot be separated.

AbstractRare coding single nucleotide variants (SNV) and short insertions or deletions (indels) contribute to Alzheimer disease (AD) genetic risk, from pathogenic variants in autosomal dominant genes to risk factors with diverse effects. In contrast, copy number variants (CNV) have been scarcely studied, with the exception of a few autosomal dominant examples, such asAPPgene duplications.We took advantage from a large case-control dataset of 22,319 exomes (4,150 early-onset AD (EOAD, onset ≤65 years), 8,519 late onset AD (LOAD) and 9,650 controls) to detect CNVs. We first identified 17 causative CNVs in autosomal dominant genes (9 novel: 7APPand 2MAPTduplications). After exclusion of carriers of these, we performed an original two-step analysis: (i) a protein-coding genome-wide analysis at the transcript level using a gene dosage strategy (EOAD versus controls) and then (ii) an integrated loss-of-function (LOF) analysis gathering short truncating variants with CNV-deletions in genes prioritized in (i) and in a list of known AD risk genes.We identified AD association with dosage of 20 genes at 4 differentlociwith a false discovery rate (FDR) below 10%, including the chr22q11.21 central region (FDR=0.0386), a region in linkage disequilibrium with theAPOElocus on chr19 (FDR=0.0271), and two single-gene loci, namelyFADS6(FDR=0.0271), andADI1(FDR=0.0916). Replication in an independent dataset made of genotyping array data from 2,780 EOAD cases, 15,222 LOAD cases and 273,979 controls was consistent with the results obtained in the discovery dataset. The integrated LOF analysis helped narrowing the region of interest to theSCARF2-KLHL22-MED15region at the 22q11.21 locus. In addition, the integrated LOF analysis highlighted rare deletions in the known AD-risk genesABCA1andABCA7that represented 10% (3/30) and 8.6% (10/115) of LOF alleles of these genes, respectively, as well as 4TYROBPdeletions. Finally, we identifyCTSBLOF alleles as candidate rare AD risk factors (p=0.0089).In conclusion, our results show that carriers of a deletion ofFADS6or a 22q11.21 deletion encompassing theSCARF2-KLHL22-MED15region, including some patients with DiGeorge syndrome, may have a higher risk of developing AD. CNVs represent a source of genomic variation that can contribute to AD etiology in new genes but also in GWAS defined-genes.

Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia.We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins [proximity extension-based (PEA) immunoassays] in a deeply-phenotyped mixed memory clinic cohort [n = 502, mean age (standard deviation, SD) = 64.1 (8.7) years, 181 female (35.4%)], including patients with Alzheimer's disease (AD, n = 213), dementia with Lewy bodies (DLB, n = 50) and frontotemporal dementia (FTD, n = 93), and controls (n = 146). Validation was assessed in independent cohorts (n = 99 PEA platform, n = 198, mass reaction monitoring-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not.We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P = 1.65 x 10-8), ZCWPW1-PILRB (rs1476679, P = 2.73 x 10-32), CTSH-CTSH (rs3784539, P = 2.88 x 10-24) and HESX1-RETN (rs186108507, P = 8.39 x 10-8), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90 x 10-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for FTD loci, either for the total sample as for analyses performed within FTD only.Protein QTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia. Genome-wide association studies have identified many risk loci for dementia, but the exact biological mechanisms by which genetic risk factors contribute to dementia remain unclear. Reus et al. demonstrate that several genetic risk variants function as protein quantitative trait loci, regulating levels of specific CSF proteins.

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

Introduction Understanding residents' workplace learning could be optimized by not only considering attending physicians' role but also the role of nurses. While previous studies described nurses' role during discrete activities (e.g. feedback), a more profound understanding of how nurses contribute to residents' learning remains warranted. Therefore, we used the educational concept of guidance and explored the extent to which residents' and nurses' perceptions align regarding nurses' guiding role and which reasons they provide for their perceptions. Methods This mixed-method study was conducted at four Dutch university medical centres in 2021. We simultaneously collected quantitative and qualitative data from 103 residents and 401 nurses through a theory-informed questionnaire with a Likert-scale and open-ended questions. We analyzed quantitative data to explore respondents' perceptions of nurses' guiding role by using anova. The thematically analyzed qualitative open comments explored respondents' reasons for their perceptions. Results Nurses indicated to provide significantly more support (p = .01) and guidance on learning from patient care (p < .01) than perceived by residents. Moreover, nurses indicated that attending physicians did not always involve them in guiding residents, whereas residents perceived nurses were being involved (p < .001). Themes suggest that nurses and residents could be divided into two groups: (i) respondents who felt that guiding was inextricably linked to good interprofessional collaboration and patient care and (ii) respondents who saw the guiding role as limited and emphasised the distinct fields of expertise between nurses and physicians. Conclusions Residents and nurses felt that nurses played an important role in guiding residents' workplace learning. However, some residents did not always perceive to be guided. To further capitalise on nurses' guiding role, we suggest that residents can be encouraged to engage in the learning opportunities nurses provide to achieve optimal team-based patient care.

BACKGROUND:Hospitals invest in Leadership Development Programs (LDPs) for physicians, assuming they benefit the organization's performance. Researchers have listed the advantages of LDPs, but knowledge of how and why organization-level outcomes are achieved is missing. OBJECTIVE:To investigate how, why and under which circumstances LDPs for physicians can impact organization-level outcomes. METHODS:We conducted a realist review, following the RAMESES guidelines. Scientific articles and grey literature published between January 2010 and March 2021 evaluating a leadership intervention for physicians in the hospital setting were considered for inclusion. The following databases were searched: Medline, PsycInfo, ERIC, Web of Science, and Academic Search Premier. Based on the included documents, we developed a LDP middle-range program theory (MRPT) consisting of Context-Mechanism-Outcome configurations (CMOs) describing how specific contexts (C) trigger certain mechanisms (M) to generate organization-level outcomes (O). RESULTS:In total, 3904 titles and abstracts and, subsequently, 100 full-text documents were inspected; 38 documents with LDPs from multiple countries informed our MRPT. The MRPT includes five CMOs that describe how LDPs can impact the organization-level outcomes categories 'culture', 'quality improvement', and 'the leadership pipeline': 'Acquiring self-insight and people skills (CMO1)', 'Intentionally building professional networks (CMO2)', 'Supporting quality improvement projects (CMO3)', 'Tailored LDP content prepares physicians (CMO4)', and 'Valuing physician leaders and organizational commitment (CMO5)'. Culture was the outcome of CMO1 and CMO2, quality improvement of CMO2 and CMO3, and the leadership pipeline of CMO2, CMO4, and CMO5. These CMOs operated within an overarching context, the leadership ecosystem, that determined realizing and sustaining organization-level outcomes. CONCLUSIONS:LDPs benefit organization-level outcomes through multiple mechanisms. Creating the contexts to trigger these mechanisms depends on the resources invested in LDPs and adequately supporting physicians. LDP providers can use the presented MRPT to guide the development of LDPs when aiming for specific organization-level outcomes.

Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer’s disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer's disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer's disease through rare variants. Here we show that a proxy Alzheimer's disease/dementia phenotype can capture known Alzheimer's disease risk genes through rare variant aggregation. We generated a proxy Alzheimer's disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer's disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer's disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer's disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer's disease/dementia can be used to identify genes associated with Alzheimer's disease through rare variant aggregation.

Many patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) use natural or traditional therapies of unproven benefit. One such therapy is ginseng root. However, in some other disease models, ginseng has proven efficacious. Ginseng improves learning and memory in rats, and reduces neuronal death following transient cerebral ischemia. These effects of ginseng have been related to increases in the expression of nerve growth factor and its high affinity receptor in the rat brain, and antioxidant actions, inter alia. Since such actions could be beneficial in ALS as well, we studied the effect of ginseng (Panax quinquefolium), 40 and 80 mg/Kg, in B6SJL-TgN(SOD1-G93A)1Gur transgenic mice. The ginseng was given in drinking water, from age 30d onwards. We measured the time to onset of signs of motor impairment, and survival. There was no difference between the two ginseng groups (n=6, 6) in either measure. However, compared to controls (n=13), there was a prolongation in onset of signs (116d vs. 94d, P<0.001), and survival (139d vs. 132d, P<0.05). These experiments lend support to the use of ginseng root in ALS. Future experiments using this model could examine for symptomatic effects of ginseng, measure the effect of specific ginsenosides (which differ between ginseng species), and elucidate their mechanisms of action.

ABSTRACTCommon SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here we show, using GWAS data from 5.4 million individuals of diverse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants.

Damaging rare variants in the TREM2 , SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer’s Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating the burden of rare damaging variants in the exomes of AD cases and controls. On a single server, we analyzed in two stages, the data from 52,270 exome sequences from several independent datasets from Europe and the United States. After comprehensive QC, Stage-1 and Stage-2 datasets comprised in total 16,396 AD cases (5,672 EOAD) and 18,107 controls with European ancestry. All detected non-synonymous and loss-of-function rare variants were prioritized by REVEL and LOFTEE, and analyzed in a per-gene burden analysis. After a Stage-1 discovery analysis, we replicated findings in an independent dataset (Stage-2). We combined the Stage-1 and Stage-2 datasets and determined, for each gene, the features of the variants that drive the burden-associations. We confirmed the AD-association of rare damaging variants SORL1, TREM2 , ABCA7 , and newly identified a significant AD-association of rare damaging variants in the ATP8B4 and ABCA1 genes. In addition, we find a strong indication for the AD-association of ADAM10 and SRC genes (Stage-2 p<0.05). For most genes, we observed a larger effect size for LOF variants compared to missense variants (Figure-A). High-impact variants in these genes are mostly extremely rare and enriched in AD patients with early ages at onset (Figure-B). We identified, for the first time, the AD-association of rare damaging variants in two genes: (i) microglial ATP8B4 which is involved in phospholipid transport, and (ii) ABCA1 which plays a critical role in lipidation of apoE thereby supporting Aβ processing. Further, we found strong evidence for the AD-association of damaging variants in ADAM10 and SRC genes. ADAM10 is involved in the proteolytic processing of APP , while SRC is a Non-Receptor Tyrosine Kinase which binds PTK2B/Pyk2 , a known AD risk factor. Together, our study provides further evidence for the role of Aβ and microglia in AD pathophysiology.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

A quarter of the world’s population is estimated to meet the criteria for metabolic syndrome, a cluster of cardiometabolic risk factors that promote development of coronary artery disease and type II diabetes, leading to increased risk of premature death and significant health costs. In this study we investigate whether the genetics associated with metabolic syndrome components mirror their phenotypic clustering. A multivariate approach that leverages genetic correlations between fasting glucose, high-density lipoprotein cholesterol, systolic blood pressure, triglycerides, and waist circumference was used; which revealed that these genetic correlations are best captured by a genetic one factor model. The common genetic factor genome-wide association study (GWAS) detects 235 associated loci, 174 more than the largest GWAS on metabolic syndrome to date. Of these loci, 53 (22.5%) overlap with loci identified for two or more metabolic syndrome components, indicating that metabolic syndrome is a complex, heterogeneous disorder. Associated loci harbour genes that show increased expression in the brain, especially in GABAergic and dopaminergic neurons. A polygenic risk score drafted from the metabolic syndrome factor GWAS predicts 5.9% of the variance in metabolic syndrome. These results provide mechanistic insights in the genetics of metabolic syndrome and suggestions for drug targets, especially fenofibrate, which has the promise of tackling multiple metabolic syndrome components.

ImportanceThe APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.ObjectiveTo determine whether rare missense variants on APOE are associated with AD risk.Design, Setting, and ParticipantsAssociation with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021.Main Outcomes and MeasuresIn primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression.ResultsA total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers.Conclusions and RelevanceIn this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.