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Haplotype-Resolved Analysis of the Filaggrin Gene Elucidates its Complex Role in Human Adaptation and Disease

ABSTRACT: The filaggrin gene (FLG) encodes a key epidermal barrier protein, and both copy number variations (CNVs) and loss-of-function (LoF) mutations are major contributors to atopic dermatitis (AD) and allergic diseases. However, the highly repetitive structure of FLG has impeded a complete understanding of its functional landscape. Analyzing 697 haplotype-resolved assemblies from ethnically diverse populations, we provide a comprehensive, nucleotide-level atlas of FLG variation. We resolved the sequences of major FLG alleles—defined by both internal repeat number and nucleotide variation—uncovering sequences with 9–20 repeats (expanding beyond the canonical R10, R11, and R12 allele groups) and delineating eight recurrent alleles (e.g., R11.1, R12.1) with ancestry-specific distributions. We identified tag variants for specific FLG alleles and refined population-specific AD burden estimates by correcting misannotated LoF variants. We detected strong signatures of local adaptation in European and southern African Khoisan-speaking populations. We further identified rs1933064 as a causal regulatory variant within an FLG enhancer and demonstrated that the ancestral A allele reduces enhancer activity and FLG expression. This allele is associated with increased AD and asthma risk but higher serum vitamin D levels, and ancient DNA analysis reveals it has risen in frequency over the past ~10,000 years—consistent with positive selection. Collectively, we present an unprecedented sequence-resolved atlas of FLG variation, revealing the contributions of distinct alleles to AD risk, vitamin D biology, and environmental adaptation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316840 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer's disease risk (odds ratio circa 2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) - predicted by molecular dynamics simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-beta secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimer's disease.

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Haplotype-Resolved Analysis of the Filaggrin Gene Elucidates its Complex Role in Human Adaptation and Disease

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