👤 Anita L Destefano

BackgroundIdentifying genetic variants conferring resilience to Alzheimer's disease and related dementia (ADRD) may hold promise for developing therapeutics.ObjectiveTo determine genetic associations with being dementia-free at age 85 (DF85).MethodsWe examined genetic associations, using whole genome sequencing data, with DF85 in three Trans-Omics for Precision Medicine cohorts and the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium. We tested common variants individually and aggregation of rare (MAF ≤ 1%) coding and non-coding variants in DF85 participants (n = 3657) against individuals who were not DF85 (n = 20,010). We verified associations using a stricter control set who developed dementia before age 85 (n = 5552).ResultsWe observed an association at Show less

Protein truncating variants (PTVs) in To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and Our results justify a debate on whether HPV carriers should be considered for clinical counseling. The online version contains supplementary material available at 10.1186/s13024-025-00907-z. Show less

There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein ( Ten single nucleotide polymorphisms within the Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the Our study does not support the role of HDL-C on risk of AD through HDL-C altered by Show less

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases. Show less

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted. Show less

Recent reports have demonstrated that adult tissue cells can be induced to pluripotency, the iPS cells, mostly with the addition of genes delivered using viruses. Also, several publications both in mouse and in human have demonstrated that spermatogonial stem cells (SSCs) from testes can convert back to embryonic stem (ES)-like cells without the addition of genes. Furthermore, these pluripotent ES-like cells can differentiate into all three germ layers and organ lineages. Thus, SSCs have great potential for cell-based, autologous organ regeneration therapy for various diseases. We obtained testes from organ donors and using 1 g pieces of tissue (biopsy size) we demonstrate that testis germ cells (putative SSCs and/or their progenitors) reprogram to pluripotency when removed from their stem cell niche and when appropriate growth factors and reagents in embryonic stem cell medium are added. In addition, our method of obtaining pluripotent ES-like cells from germ cells is simpler than the described methods and may be more suitable if this procedure is developed for the clinic to obtain pluripotent cells to cure disease. Show less