TOMM40 and APOC1 variants differentiate the impacts of the APOE ε4 allele on Alzheimer's disease risk across sexes, ages, and ancestries.

INTRODUCTION: The variability in apolipoprotein E (APOE) ε4-attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants. METHODS: We examined associations of compound genotypes (CompGs) comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD-affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages. RESULTS: The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4-bearing CompGs define lower- and higher-AD-risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear-with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between-patterns across ages. DISCUSSION: The ε4-bearing CompGs have a potential to differentiate biological mechanisms of sex-, age-, and ancestry-specific AD risks and serve as AD biomarkers. Highlights: Younger White women carrying the lower-risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher-risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.

Exome-Wide Association Study Identified Clusters of Pleiotropic Genetic Associations with Alzheimer's Disease and Thirteen Cardiovascular Traits.

Alzheimer's disease (AD) and cardiovascular traits might share underlying causes. We sought to identify clusters of cardiovascular traits that share genetic factors with AD. We conducted a univariate exome-wide association study and pair-wise pleiotropic analysis focused on AD and 16 cardiovascular traits-6 diseases and 10 cardio-metabolic risk factors-for 188,260 UK biobank participants. Our analysis pinpointed nine genetic markers in the APOE gene region and four loci mapped to the CDK11, OBP2B, TPM1, and SMARCA4 genes, which demonstrated associations with AD at p ≤ 5 × 10-4 and pleiotropic associations at p ≤ 5 × 10-8. Using hierarchical cluster analysis, we grouped the phenotypes from these pleiotropic associations into seven clusters. Lipids were divided into three clusters: low-density lipoprotein and total cholesterol, high-density lipoprotein cholesterol, and triglycerides. This split might differentiate the lipid-related mechanisms of AD. The clustering of body mass index (BMI) with weight but not height indicates that weight defines BMI-AD pleiotropy. The remaining two clusters included (i) coronary heart disease and myocardial infarction; and (ii) hypertension, diabetes mellitus (DM), systolic and diastolic blood pressure. We found that all AD protective alleles were associated with larger weight and higher DM risk. Three of the four (75%) clusters of traits, which were significantly correlated with AD, demonstrated antagonistic genetic heterogeneity, characterized by different directions of the genetic associations and trait correlations. Our findings suggest that shared genetic factors between AD and cardiovascular traits mostly affect them in an antagonistic manner.

Prevailing Antagonistic Risks in Pleiotropic Associations with Alzheimer's Disease and Diabetes.

BACKGROUND: The lack of efficient preventive interventions against Alzheimer's disease (AD) calls for identifying efficient modifiable risk factors for AD. As diabetes shares many pathological processes with AD, including accumulation of amyloid plaques and neurofibrillary tangles, insulin resistance, and impaired glucose metabolism, diabetes is thought to be a potentially modifiable risk factor for AD. Mounting evidence suggests that links between AD and diabetes may be more complex than previously believed. OBJECTIVE: To examine the pleiotropic architecture of AD and diabetes mellitus (DM). METHODS: Univariate and pleiotropic analyses were performed following the discovery-replication strategy using individual-level data from 10 large-scale studies. RESULTS: We report a potentially novel pleiotropic NOTCH2 gene, with a minor allele of rs5025718 associated with increased risks of both AD and DM. We confirm previously identified antagonistic associations of the same variants with the risks of AD and DM in the HLA and APOE gene clusters. We show multiple antagonistic associations of the same variants with AD and DM in the HLA cluster, which were not explained by the lead SNP in this cluster. Although the ɛ2 and ɛ4 alleles played a major role in the antagonistic associations with AD and DM in the APOE cluster, we identified non-overlapping SNPs in this cluster, which were adversely and beneficially associated with AD and DM independently of the ɛ2 and ɛ4 alleles. CONCLUSION: This study emphasizes differences and similarities in the heterogeneous genetic architectures of AD and DM, which may differentiate the pathogenic mechanisms of these diseases.

Exogenous exposures shape genetic predisposition to lipids, Alzheimer's, and coronary heart disease in the MLXIPL gene locus.

Associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer's (AD) and coronary heart disease (CHD) and potentially causal mediation effects of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), were examined in two samples of European ancestry from the US (22,712 individuals 587/2,608 AD/CHD cases) and the UK Biobank (UKB) (232,341 individuals; 809/15,269 AD/CHD cases). Our results suggest that these associations can be regulated by several biological mechanisms and shaped by exogenous exposures. Two patterns of associations (represented by rs17145750 and rs6967028) were identified. Minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG (lower HDL-C) and high HDL-C (lower TG) levels, respectively. The primary association explained ~50% of the secondary one suggesting partly independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly higher in the US vs. UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect through TG on AD risk in the UKB only (ßIE = 0.015, pIE = 1.9 × 10-3), which suggests protective effects of high TG levels against AD, likely shaped by exogenous exposures. Also, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C in the associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (ßIE = 0.019, pIE = 8.6 × 10-4). This trade-off suggests different roles of triglyceride mediated mechanisms in the pathogenesis of AD and CHD.

Associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease biomarkers.

Capturing the genetic architecture of Alzheimer's disease (AD) is challenging because of the complex interplay of genetic and non-genetic factors in its etiology. It has been suggested that AD biomarkers may improve the characterization of AD pathology and its genetic architecture. Most studies have focused on connections of individual genetic variants with AD biomarkers, whereas the role of combinations of genetic variants is substantially underexplored. We examined the associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with cerebrospinal fluid (CSF) and plasma amyloid ß (Aß40 and Aß42) and tau biomarkers. Our findings support associations of the ε4 alleles with both plasma and CSF Aß42 and CSF tau, and the ε2 alleles with baseline, but not longitudinal, CSF Aß42 measurements. We found that the ε4-bearing polygenic profiles conferring higher and lower AD risks are differentially associated with tau but not Aß42. Modulation of the effect of the ε4 alleles by TOMM40 and APOC1 variants indicates the potential genetic mechanism of differential roles of Aß and tau in AD pathogenesis.

APOE ɛ4 allele and TOMM40-APOC1 variants jointly contribute to survival to older ages.

Age-related diseases characteristic of post-reproductive life, aging, and life span are the examples of polygenic non-Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non-carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non-carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid- and immunity-related mechanisms, whereas the AD risk, can be driven by the AD-biomarker-related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care.

APOE alleles modulate associations of plasma metabolites with variants from multiple genes on chromosome 19q13.3.

The APOE ε2, ε3, and ε4 alleles differentially impact various complex diseases and traits. We examined whether these alleles modulated associations of 94 single-nucleotide polymorphisms (SNPs) harbored by 26 genes in 19q13.3 region with 217 plasma metabolites using Framingham Heart Study data. The analyses were performed in the E2 (ε2ε2 or ε2ε3 genotype), E3 (ε3ε3 genotype), and E4 (ε3ε4 or ε4ε4 genotype) groups separately. We identified 31, 17, and 22 polymorphism-metabolite associations in the E2, E3, and E4 groups, respectively, at a false discovery rate P FDR < 0.05. These entailed 51 and 19 associations with 20 lipid and 12 polar analytes. Contrasting the effect sizes between the analyzed groups showed 20 associations with group-specific effects at Bonferroni-adjusted P < 7.14E-04. Three associations with glutamic acid or dimethylglycine had significantly larger effects in the E2 than E3 group and 12 associations with triacylglycerol 56:5, lysophosphatidylethanolamines 16:0, 18:0, 20:4, or phosphatidylcholine 38:6 had significantly larger effects in the E2 than E4 group. Two associations with isocitrate or propionate and three associations with phosphatidylcholines 32:0, 32:1, or 34:0 had significantly larger effects in the E4 than E3 group. Nine of 70 SNP-metabolite associations identified in either E2, E3, or E4 groups attained P FDR < 0.05 in the pooled sample of these groups. However, none of them were among the 20 group-specific associations. Consistent with the evolutionary history of the APOE alleles, plasma metabolites showed higher APOE-cluster-related variations in the E4 than E2 and E3 groups. Pathway enrichment mainly highlighted lipids and amino acids metabolism and citrate cycle, which can be differentially impacted by the APOE alleles. These novel findings expand insights into the genetic heterogeneity of plasma metabolites and highlight the importance of the APOE-allele-stratified genetic analyses of the APOE-related diseases and traits.

Mediation of the APOE associations with Alzheimer's and coronary heart diseases through body mass index and lipids.

The APOE ε2/ε3/ε4 polymorphism is associated with multiple non-Mendelian traits, including high- (HDL-C) and low- (LDL-C) density lipoprotein cholesterol, triglycerides, body mass index (BMI), coronary heart disease (CHD), and Alzheimer's disease (AD). Lipids and BMI are risk factors for AD and CHD. Causal connections between the ε2 and ε4 alleles and these traits remain, however, poorly understood. We leverage comprehensive analyses of longitudinal data from four studies to examine potentially causal heterogeneous connections between these alleles, lipids, BMI, and diseases. We emphasize mutual mediation roles of lipids and BMI in their associations with the ε2 and ε4 alleles and their mediation roles in the associations of these alleles with AD and CHD. We confirmed previously reported significant univariate associations of these alleles with each trait, except CHD. We found, however, that most of the univariate- and mediation-analysis associations were affected by antagonistic heterogeneity/mediation. The mutual mediation analysis identified the associations of the APOE alleles with LDL-C as the least heterogeneous. The ε2 and ε4 alleles were associated with CHD through lipids, led by beneficial (ßIE = - 0.071, pIE = 2.28 × 10-10) and adverse (ßIE = 0.019, pIE = 7.37 × 10-6) associations, respectively, through LDL-C. Both these alleles were adversely associated with CHD through triglycerides. For AD, only BMI partially mediated the adverse association of the ε4 allele with AD (ßIE = 0.016, pIE = 2.09 × 10-2). Our results suggest different roles of BMI and lipids in the AD and CHD pathogeneses. More comprehensive studies of causal connections between genetic variants and non-Mendelian traits are required as they can be critically affected by heterogeneous antagonistic relationships.

Pleiotropic predisposition to Alzheimer's disease and educational attainment: insights from the summary statistics analysis.

Epidemiological studies report beneficial associations of higher educational attainment (EDU) with Alzheimer's disease (AD). Prior genome-wide association studies (GWAS) also reported variants associated with AD and EDU separately. The analysis of pleiotropic associations with these phenotypes may shed light on EDU-related protection against AD. We performed pleiotropic meta-analyses using Fisher's method and omnibus test applied to summary statistics for single nucleotide polymorphisms (SNPs) associated with AD and EDU in large-scale univariate GWAS at suggestive-effect (5 × 10-8 < p < 0.1) and genome-wide (p ≤ 5 × 10-8) significance levels. We report 53 SNPs that attained p ≤ 5 × 10-8 at least in one of the pleiotropic meta-analyses and were reported in the univariate GWAS at 5 × 10-8 < p < 0.1. Of them, there were 46 pleiotropic SNPs according to Fisher's method. Additionally, Fisher's method identified 25 of 206 SNPs with pleiotropic effects, which attained p ≤ 5 × 10-8 in the univariate GWAS. We showed that a large fraction of the pleiotropic associations was affected by a counterintuitive phenomenon of antagonistic genetic heterogeneity, which explains the increase, rather than decrease, of the significance of the pleiotropic associations in the omnibus test. Functional enrichment analysis showed that apart from cancers, gene set harboring the non-pleiotropic SNPs was characterized by late-onset AD and neurodevelopmental disorders. The pleiotropic gene set was characterized by a broad spectrum of progressive neurological and neuromuscular diseases and immune-mediated conditions, including progressive motor neuropathy, multiple sclerosis, Parkinson's disease, and severe AD. Our results suggest that disentangling genes harboring variants with and without pleiotropic associations with AD and EDU is promising for dissecting heterogeneity in biological mechanisms of AD.

Corrigendum: Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.

[This corrects the article on p. 179 in vol. 7, PMID: 27790247.].

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.

Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.