rs10421247 (MARK4/NKPD1): Biomarkers & Alzheimer's Risk

Key takeaways

• rs10421247, near MARK4 and NKPD1, was identified in a large study of 35 blood and urine biomarkers in over 363,000 UK Biobank participants
• A genome-wide Alzheimer's disease meta-analysis of 71,880 cases and 383,378 controls placed this region among 29 genome-wide significant risk loci
• The Alzheimer's study found that its full set of 29 risk-associated loci showed gene enrichment in immune-related tissues including microglia (brain-resident immune cells), spleen, and liver
• GTEx expression data link this variant to reduced gene activity in visceral abdominal fat and in aortic tissue

What the research says A genome-wide association study of 35 blood and urine biomarkers in 363,228 UK Biobank participants identified 1,857 associated loci containing 3,374 fine-mapped associations, placing this region among a catalogued set of clinically measured laboratory trait associations; Mendelian randomization across that study identified 51 causal biomarker-disease relationships PMID 33462484. A three-phase Alzheimer's disease meta-analysis combining 24,087 clinically diagnosed late-onset AD cases with a UK Biobank AD-by-proxy phenotype derived from parental diagnoses (genetic correlation rg=0.81 between proxy and clinical AD) - totalling 71,880 cases and 383,378 controls - identified 29 genome-wide significant risk loci implicating 215 potential causative genes, with the overall risk-gene set enriched for expression in immune-related tissues including microglia, spleen, and liver PMID 30617256. GTEx v11 expression-QTL analysis across 953 donors independently links this variant to reduced expression of two genes in distinct peripheral tissues GTEx Portal.

Reported associations

• Blood and urine biomarkers: This locus was among 1,857 biomarker-associated regions in a UK Biobank GWAS of 35 clinical laboratory measurements (n=363,228), a study that also identified large-effect protein-altering variant associations and applied Bonferroni-corrected significance thresholds (p<5×10^-9) PMID 33462484
• Alzheimer's disease risk: This region was included among 29 genome-wide significant (p<5×10^-8) loci identified in a meta-analysis of clinically diagnosed AD and an AD-by-proxy phenotype; the study's gene-set analyses indicated biological mechanisms involving lipid-related processes and degradation of amyloid precursor proteins across the identified risk loci PMID 30617256

Evidence quality The biomarker study is a large-scale GWAS (n=363,228 unrelated participants) with analysis stratified across five ancestry groups (White British, non-British White, African, South Asian, and East Asian) followed by meta-analysis; LD Score regression intercepts ranged from 0.999 to 1.137 across all 35 traits, indicating well-controlled population stratification PMID 33462484. The Alzheimer's disease meta-analysis used a three-phase design totalling 455,258 individuals of European ancestry; the authors note that including the proxy-phenotype sample may underestimate true genetic effect sizes because proxy cases include individuals who may never develop AD, though the large combined sample substantially increases power for detection of common risk variants PMID 30617256. GTEx expression-QTL data (953 donors, cis-window, FDR<0.05) provide mechanistic tissue-level context only and do not establish disease outcomes. Both GWAS were conducted predominantly in European-ancestry populations, which may limit generalizability to other ancestries. No direct replication studies for this specific variant are described in the provided evidence.

Tissue-specific expression effects

• ENSG00000302518: This variant is associated with reduced expression of this gene in adipose visceral omentum (the fat tissue layer surrounding the abdominal organs) GTEx Portal
• CCDC61: This variant is associated with reduced expression in aorta tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.