Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

Jansen, I.; Savage, J.; Watanabe, K.; Bryois, J.; Williams, D.; Steinberg, S.; Sealock, J.; Karlsson, I.; Hagg, S.; Athanasiu, L.; Voyle, N.; Proitsi, P.; Witoelar, A.; Stringer, S.; Aarsland, D.; Almdahl, I.; Andersen, F.; Bergh, S.; Bettella, F.; Bjornsson, S.; Braekhus, A.; Brathen, G.; de Leeuw, C.; Desikan, R.; Djurovic, S.; Dumitrescu, L.; Fladby, T.; Homan, T.; Jonsson, P.; Rongve, A.; Saltvedt, I.; Sando, S.; Selbak, G.; Skene, N.; Snaedal, J.; Stordal, E.; Ulstein, I.; Wang, Y.; White, L.; Hjerling-Leffler, J.; Sullivan, P.; van der Flier, W.; Dobson, R.; Davis, L.; Stefansson, H.; St

doi:10.1101/258533

Home/Archive/bioRxiv

bioRxiv · 10.1101/258533

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk

View original source ↗Export metadata ↓

Abstract

Late onset Alzheimers disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Jansen, I., Savage, J., Watanabe, K., Bryois, J., Williams, D., Steinberg, S., Sealock, J., Karlsson, I., Hagg, S., Athanasiu, L., Voyle, N., Proitsi, P., Witoelar, A., Stringer, S., Aarsland, D., Almdahl, I., Andersen, F., Bergh, S., Bettella, F., Bjornsson, S., Braekhus, A., Brathen, G., de Leeuw, C., Desikan, R., Djurovic, S., Dumitrescu, L., Fladby, T., Homan, T., Jonsson, P., Rongve, A., Saltvedt, I., Sando, S., Selbak, G., Skene, N., Snaedal, J., Stordal, E., Ulstein, I., Wang, Y., White, L., Hjerling-Leffler, J., Sullivan, P., van der Flier, W., Dobson, R., Davis, L., Stefansson, H., St. 2018-02-20. Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer’s disease risk. https://doi.org/10.1101/258533

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Cellular context shapes the transcriptomic impact of somatic variants

Somatic SNVs are commonly prioritized by recurrence or sequence annotation, leaving the molecular consequences of private variants unresolved. We developed PrismSNV and Ligo-Seq, a single-cell full-length transcriptome sequencing platform, to quantify transcriptomic displacement associated with within-cell SNV-state toggling. Across 26 samples from three cancer types, more than 60% of candidate SNVs showed significant cell-type-specific displacement with over 30% variation in magnitude. Sequence-based deleteriousness was poorly aligned with cellular displacement, and fewer than 3% of top-displacement SNVs across six tumor types were catalogued in ClinVar. Displacement was strongest in transcriptionally plastic, less differentiated states. Analysis of 655,349 CD4+ T-cell transcriptomes further showed that SNV-gene associations changed in magnitude and sometimes direction during activation. Lack of recurrence or clinical annotation does not imply transcriptomic inertness; variant impact is shaped by cellular context rather than sequence alone, establishing the variant-cell pair as a critical unit for interpreting somatic variation.

genetics↗

bioRxiv2026

Genetic and Epigenetic Landscape of Self-Identified Hispanics/Latino in All Of Us

Human genetic studies still underrepresent many populations, limiting discovery and interpretation of medically relevant variation. Extensive admixture in self-identified Hispanic/Latino populations increases the need for representative reference data and ancestry-aware interpretation of medically relevant variation. We used long-read sequencing to analyze genetic variation, ancestry, and DNA methylation in 1,490 self-identified Hispanic/Latino participants from the All of Us Research Program. We identified 10 million novel variants and more than 100 candidate phenotype associations, with fine-mapping prioritizing structural variants over nearby single-nucleotide variants in more than half. We linked 3,329 tandem repeats to DNA methylation, resolved widespread allele-specific methylation, and identified ancestry-linked regulation across paralogous genes. These results reveal previously inaccessible genetic and regulatory variation and show the value of long-read sequencing for diverse populations.

genetics↗

bioRxiv2026

The genetic architecture of human DNA methylome variation

Population DNA methylome analyses remain largely confined to reference-defined genomic space despite extensive human genetic diversity. A central challenge is therefore to define comparable methylation phenotypes across diverse genomes and map the genetic architecture of methylome variation. Here, using 460 haplotypes from the Human Pangenome Reference Consortium Release 2, we develop two complementary pangenome-based frameworks: one compares methylation within homologous regions while retaining haplotype-specific structural configuration and CpG content; the other represents CpG island (CGI) variation at homologous loci as sequence-resolved alleles. We identified 47,039 CGI alleles, including 8,040 absent from CHM13; 62% were attributable to structural variants and 31% to small variants. Through local genealogies, we reconstructed CGI gain, loss and turnover, revealing how present-day methylation differences align with CGI evolutionary trajectories. We found that genome-wide, methylation variability was buffered against genetic diversity across more than 90% of the genome, with exceptions at extreme nucleotide diversity and locally around structural variants. Our methylation framework enabled population-scale allele-aware methylation quantitative trait locus (mQTL) mapping into non-reference and structurally complex sequence, where mQTL-associated intervals were enriched. mQTLs linked methylation to transcriptomic phenotypes, population differentiation and complex traits, supporting 8% of population differentially methylated regions and colocalizing with more than half of genome-wide association study loci. Together, our study redefines human methylome analysis and our findings reveal a genome-wide architecture of genetic-epigenetic coupling, reshaping how methylation variation is interpreted across human development and disease.

genetics↗