Biomedical subjects

Christoph Lange

Publications and source records attributed to Christoph Lange.

3 recordsLinked to original sources

PubMed2026

Polygenic risk scores associate with asthma phenotypes and proteomic analyses implicate IL1R1 in two family-based studies.

Despite its high prevalence and the discovery of hundreds of genetic associations, the genetic determinants and heterogeneous manifestations of asthma remain incompletely understood. Incorporating polygenic risk scores (PRS) into asthma research offers a powerful approach to quantify inherited susceptibility, refine risk profiles, and advance mechanistic understanding of disease development. For this study, we leveraged whole-genome sequencing (WGS) data from two family-based cohorts of childhood asthma - the Genetics of Asthma in Costa Rica Study (GACRS) and the Childhood Asthma Management Program (CAMP) - to examine the transmission profiles of externally derived asthma PRS and their associations with clinical phenotypes in children with asthma. To further elucidate molecular mechanisms, we integrated large-scale external genome-wide association study (GWAS) summary statistics and genetic prediction models of protein abundance in a two-step proteome-wide association study (PWAS) of asthma. Our findings provide robust evidence supporting the validity of externally derived asthma PRS (asthma PRS association p-value p = 10-24 [GACRS and CAMP trios combined] for the Global Biobank Meta-analysis Initiative [GBMI]) and reveal consistent associations with spirometry measures and atopy markers across both studies, as 13 of 21 traits (62%) were significantly associated with the GBMI-PRS in the meta-analysis after multiple-testing correction. Moreover, the results of the integrative proteomic analysis implicate IL-1 signaling in the etiology of asthma, reinforcing the candidacy of IL1R1 antagonists for drug repurposing.

Journal Article↗

PubMed2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans↗

PubMed2025

Matching Heterogeneous Cohorts by Projected Principal Components Reveals Two Novel Alzheimer's Disease-Associated Genes in the Hispanic Population.

Alzheimer's disease (AD) is the most common form of dementia in elderly, affecting 6.9 million individuals in the United States. Some studies have suggested the prevalence of AD is greater in individuals who self-identify as Hispanic. Focused results are relevant for personalized and equitable clinical interventions. Ethnicity as a stratifying tool in genetic studies is often accompanied by genomic inflation due to heterogeneity. In this study, we report GWAS and meta-analyses conducted among NIAGADS subjects who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components, with and without age and sex. In Hispanic NIAGADS subjects, we identified a common variant in PIEZO2 that was protective for AD with a p-value just beyond genome-wide significance (p = 5.4*10-8). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 (RGS6/PSEN1), rs192423465 (ASPSCR1), and rs935208076 (GDAP2), which were also nominally significant in AoU sub-cohorts. We thus demonstrate an efficient way to select subjects from large heterogeneous biobank cohorts who are genetically similar to a smaller disease-specific cohort, yielding novel disease-relevant findings.

Journal Article↗