rs3865444

badMag 5.5

This is a upstream gene variant variant in the CD33 gene.

Key Literature Trait Associations

CD33 expression on monocytes

The C allele of rs3865444 is one of the strongest known cis-regulatory variants for an immune cell protein, associated with dramatically higher CD33 surface expression on CD14+ monocytes and CD33+HLA-DR+ cells. Orrù et al. (2020) reported association p-values below 10⁻¹⁴⁴ in a Sardinian cohort study of immune cell traits. This effect is mediated through increased inclusion of CD33 exon 2, producing more full-length CD33 protein capable of sialic acid binding and immune inhibitory signaling. This pQTL/splicing effect is considered the mechanistic bridge between rs3865444 and Alzheimer's disease susceptibility.

Orrù V et al. “Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.” Nature Genetics 52(10):1036-1045 (2020)

Allele C

OR —

β 1.219

p 1.0e-144

N 3,757

Large GWAS

Sardinian

Raj T et al. “CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer's disease susceptibility.” Human Molecular Genetics (2014)

Allele C

OR —

p 2.4e-60

N 398

Small GWAS

multi-ancestry

Alzheimer's Disease

The C allele of rs3865444 is associated with modestly increased risk of late-onset Alzheimer's disease, with meta-analyses reporting an odds ratio of approximately 1.06–1.11 per C allele, while the A allele is protective (OR ~0.94 in large Caucasian cohorts). The association was first confirmed at genome-wide significance (p=1.6×10⁻⁹) by Naj et al. (2011) and has been replicated in multiple large GWAS consortia. The effect appears strongest in European-ancestry populations; some Asian cohorts show no significant association, and one smaller meta-analysis found no overall effect, highlighting population heterogeneity. The mechanistic basis involves increased full-length CD33 expression on microglia, which suppresses amyloid-beta clearance.

Jiang YT et al. “Meta-analysis of the association between CD33 and Alzheimer's disease.” Annals of Translational Medicine (2018)

Allele C

OR 0.94

p 1.0e-2

N 127,435

Meta-analysis

multi-ancestry (Caucasian and Asian)

Jansen IE et al. “Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.” Nature Genetics 51(3):404-413 (2019)

Allele C

OR —

p 5.0e-8

N 455,258

Meta-analysisSmall GWAS

European

Li X et al. “CD33 rs3865444 Polymorphism Contributes to Alzheimer's Disease Susceptibility in Chinese, European, and North American Populations.” Molecular Neurobiology (2015)

Allele C

OR 0.97

p 2.6e-1

N 86,759

Preliminary work

multi-ancestry

Raj T et al. “CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer's disease susceptibility.” Human Molecular Genetics (2014)

Allele C

OR —

p 2.4e-60

N 398

Small GWAS

multi-ancestry

Naj AC et al. “Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.” Nature Genetics 43(5):436-41 (2011)

Allele C

OR —

p 1.6e-9

Large GWAS

European

Monocyte count

The A allele of rs3865444 is robustly associated with lower circulating monocyte counts in large population-based GWAS, consistent with the known role of CD33 as a myeloid differentiation and survival factor. The association has been reported at genome-wide significance in cohorts of over 173,000 individuals. This aligns with the functional finding that the A allele reduces full-length CD33 surface expression, thereby altering myeloid cell homeostasis. The effect is modest in absolute terms (beta ~−0.017 to −0.018 SD units) but is highly reproducible across European cohorts.

Astle WJ et al. “The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.” Cell 167(5):1415-1429.e19 (2016)

Allele A

OR —

β -0.017

p 9.0e-15

N 173,480

Large GWAS

European

Vuckovic D et al. “The Polygenic and Monogenic Basis of Blood Traits and Diseases.” Cell 182(5):1214-1231.e11 (2020)

Allele A

OR —

β -0.018

p 1.0e-19

Large GWAS

multi-ancestry

Lymphocyte count

The A allele at rs3865444 is associated with modestly lower lymphocyte counts at genome-wide significance in large GWAS of blood cell traits. The effect (beta ~−0.020 to −0.024 SD units) is consistent across multiple large cohort studies. Although CD33 is primarily expressed on myeloid cells, its broader immunoregulatory role may indirectly influence lymphocyte dynamics, and this locus has been replicated in independent datasets exceeding 100,000 participants.

Vuckovic D et al. “The Polygenic and Monogenic Basis of Blood Traits and Diseases.” Cell 182(5):1214-1231.e11 (2020)

Allele A

OR —

β -0.024

p 1.0e-24

Large GWAS

multi-ancestry

Astle WJ et al. “The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.” Cell 167(5):1415-1429.e19 (2016)

Allele A

OR —

β -0.021

p 1.0e-24

N 173,480

Large GWAS

European

White blood cell count

The A allele at rs3865444 is associated with lower total white blood cell (leukocyte) count at genome-wide significance. This was established in the large Astle et al. (2016) GWAS of 173,480 participants (beta ~−0.024, p=2×10⁻¹⁰). The association likely reflects the combined reduction in monocyte and lymphocyte counts attributable to this locus, consistent with CD33's immunoregulatory function across multiple leukocyte lineages.

Astle WJ et al. “The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.” Cell 167(5):1415-1429.e19 (2016)

Allele A

OR —

β -0.024

p 2.0e-10

N 173,480

Large GWAS

European

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GWAS Catalog Trait Associations (18)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

platelet crit

Vuckovic D et al. “The Polygenic and Monogenic Basis of Blood Traits and Diseases.” Cell 182(5):1214-1231.e11 (2020)

Allele A

OR 0.03

p 1.0e-26

N 408,112

Large GWAS

European

leukocyte quantity

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele C

OR 0.04

p 3.0e-26

N 545,812

Major Consortium StudyLarge GWAS

multi-ancestry

Astle WJ et al. “The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.” Cell 167(5):1415-1429.e19 (2016)

Allele C

OR 0.02

p 2.0e-10

N 172,435

Large GWAS

European

CD33 molecule amount

Surapaneni A et al. “Identification of 969 protein quantitative trait loci in an African American population with kidney disease attributed to hypertension.” Kidney International 102(5):1167-1177 (2022)

Allele A

OR 1.09

p 6.0e-26

N 466

Small GWAS

African American or Afro-Caribbean

lymphocyte count

Vuckovic D et al. “The Polygenic and Monogenic Basis of Blood Traits and Diseases.” Cell 182(5):1214-1231.e11 (2020)

Allele A

OR 0.02

p 1.0e-24

N 408,112

Large GWAS

European

Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)

Allele A

OR 0.02

p 8.0e-16

N 445,573

Large GWAS

multi-ancestry

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele A

OR 0.02

p 5.0e-24

N 394,642

Large GWAS

European

Red cell distribution width

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele C

OR 0.03

p 4.0e-23

N 380,796

Major Consortium StudyLarge GWAS

European

Chen MH et al. “Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.” Cell 182(5):1198-1213.e14 (2020)

Allele C

OR 0.01

p 1.0e-11

N 531,774

Large GWAS

European

monocyte count

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele A

OR 0.02

p 8.0e-19

N 394,642

Large GWAS

European

Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)

Allele A

OR 0.02

p 3.0e-14

N 444,975

Large GWAS

multi-ancestry

Vuckovic D et al. “The Polygenic and Monogenic Basis of Blood Traits and Diseases.” Cell 182(5):1214-1231.e11 (2020)

Allele A

OR 0.02

p 9.0e-15

N 408,112

Large GWAS

European

C-reactive protein measurement

Han X et al. “Using Mendelian randomization to evaluate the causal relationship between serum C-reactive protein levels and age-related macular degeneration.” European Journal of Epidemiology 35(2):139-146 (2020)

Allele C

OR 0.02

p 4.0e-18

N 418,642

Large GWAS

European

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele C

OR 0.02

p 2.0e-17

N 394,642

Large GWAS

European

HbA1c measurement

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele C

OR 0.03

p 4.0e-18

N 338,640

Major Consortium StudyLarge GWAS

European

mean corpuscular hemoglobin concentration

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele C

OR 0.02

p 2.0e-16

N 407,345

Major Consortium StudyLarge GWAS

European

bilirubin measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele A

OR 0.01

p 4.0e-14

N 394,642

Large GWAS

European

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Research that mentions this SNP (4)

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F‐box/ LRR ‐repeat protein 7 is genetically associated with Alzheimer's disease

AssociationN=5,300Giuseppe Tosto et al.(2015)· Annals of Clinical and Translational Neurology

A genome-wide association study of 4,514 unrelated Caribbean Hispanics identified a novel locus rs75002042 in FBXL7 associated with late-onset Alzheimer's disease (OR=0.61, p=6.19E-09), confirmed in an expanded cohort of 5,300 subjects (OR=0.63, p=4.7E-08). The study also identified rs7431992 in CACNA2D3 (OR=1.59, p=1.99E-08) and replicated six previously known LOAD loci.

Traits studied:Alzheimer diseaseLate-onset Alzheimer's disease (LOAD)

PubMed DOI Metascience Observatory

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Genetic Susceptibility for Alzheimer Disease Neuritic Plaque Pathology

AssociationN=725Joshua M. Shulman et al.(2013)· JAMA Neurology

A genome-wide association study of 725 deceased subjects identified genetic susceptibility loci for Alzheimer's disease neuritic plaque pathology. Beyond APOE and CR1, the study found ABCA7 (rs3764650, p=0.03) and CD2AP (rs9349407, p=0.03) associated with increased neuritic plaque burden. Notably, a novel APP locus variant (rs2829887, p=3.3×10⁻⁶) was associated with neuritic plaques and β-amyloid load in postmortem samples and independently replicated in cognitively normal PET imaging cohorts, implicating common genetic variation in amyloid pathology at pre-symptomatic AD stages.

Traits studied:Alzheimer's diseasecognitive declinefibrillar β-amyloid depositionmild cognitive impairmentneuritic plaque pathologyβ-amyloid load

PubMed DOI Metascience Observatory

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The prevalence of CD33 and MS4A6A variant in Chinese Han population with Alzheimer’s disease

AssociationN=383Yu-Lei Deng et al.(2012)· Human Genetics

A case-control study of 190 AD patients and 193 controls in the Chinese Han population found that the T allele of rs3865444 in CD33 (OR=0.480, p<0.001) and the C allele of rs610932 in MS4A6A (OR=0.622, p=0.001) are associated with increased Alzheimer's disease risk, confirming previous GWAS findings in a non-Caucasian population.

Traits studied:Alzheimer's disease

PubMed DOI Metascience Observatory

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A Comprehensive Genetic Association Study of Alzheimer Disease in African Americans

AssociationN=1,009Logue MW et al.(2011)· Archives of Neurology

This comprehensive genome-wide association study examined genetic variants contributing to late-onset Alzheimer's disease (AD) in 513 African American cases and 496 controls, plus replication in 5 white cohorts. The APOE ε4 allele showed strong association (P=9.69×10⁻²³), and after adjusting for APOE, rs6859 in PVRL2 remained significantly associated (P=0.0087). The study found associations with variants in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, though effect directions sometimes differed from white populations. Novel associations with suggestive evidence were identified in PROX1, CNTNAP2, STK24, and other genes, though not replicated in whites.

rs3865444

Key Literature Trait Associations

CD33 expression on monocytes

Alzheimer's Disease

Monocyte count

Lymphocyte count

White blood cell count

GWAS Catalog Trait Associations (18)

platelet crit

leukocyte quantity

CD33 molecule amount

lymphocyte count

Red cell distribution width

monocyte count

C-reactive protein measurement

HbA1c measurement

mean corpuscular hemoglobin concentration

bilirubin measurement

Research that mentions this SNP (4)

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