Young Strokes Linked to Blood-Type Genes: Large Study Finds ABO Variants and Clotting Risk Drive Early-Onset Ischemic Stroke

A large, international genetic study shows that common variants in the ABO blood-group locus, especially alleles tagging blood subgroup A1, increase risk for early-onset ischemic stroke, while the O1 subgroup appears protective. The same ABO signals are tied to higher levels of clotting proteins and to venous thromboembolism, supporting a model in which prothrombotic mechanisms play a stronger role in strokes at younger ages than in strokes that occur later in life.

Why this study matters, in one line

If genes that influence how “sticky” blood proteins are can raise stroke risk in young adults, then exploring clotting biology could open new paths for prevention and tailored care for people who have strokes early in life.

When stroke happens too early

A stroke at age 40 or 50 lands like a sucker punch. It can end careers, change family roles, and trigger years of disability at an age when people usually expect to be at their peak. Clinicians and scientists have long recognized that strokes in younger adults often have different causes than strokes in their seventies and eighties, yet most genetic research has focused on older patients. The International Early Onset Stroke Genetics Consortium pooled data from dozens of studies to ask a simple but crucial question: are there common genetic variants that specifically raise the risk of ischemic stroke in people younger than 60, and do those variants point to biological mechanisms we can act on?

The problem the researchers wanted to solve

Most large genetic studies of stroke have emphasized late-onset cases, which are often driven by progressive atherosclerosis. By contrast, early-onset ischemic stroke may rely more on nonatherosclerotic pathways, including a tendency for abnormal blood clotting. The gap in knowledge was whether common genetic variants—those shared by many people—contribute differently to stroke when it happens early in life versus late, and whether these variants reveal disease mechanisms that are more actionable for younger patients.

The approach, in plain language

The team performed a genome-wide association meta-analysis that pooled genetic data from 48 studies around the world. After quality control, the analysis included 16,730 early-onset ischemic stroke cases (people with first stroke between ages 18 and 59) and 599,237 nonstroke controls. Most genetic data were imputed to the TOPMed reference panel and analyzed on the human genome build hg38, and models adjusted for ancestry and other confounders so the results reflected genetic effects rather than population differences. The researchers ran two main analyses: a transethnic meta-analysis to maximize discovery power, and a European-only analysis to compare directly with well-studied late-onset stroke datasets. They also compared effect sizes to a late-onset stroke cohort and tested whether genetic risk for venous thromboembolism (VTE), a condition of dangerous clots, predicted early stroke risk.

The big discovery — ABO genes stand out

The strongest and clearest finding was at the ABO gene, which determines blood groups A, B, AB, and O. Two common variants in ABO reached genome-wide significance and map to specific ABO subgroups:

• A variant tagging the O1 subgroup (rs529565) was protective against early-onset stroke, with an odds ratio (OR) of 0.88 (95% CI 0.85–0.91) in the European-only analysis. This protective effect was stronger for early-onset stroke than for late-onset stroke, where the OR was about 0.96.
• A variant tagging the A1 subgroup (rs635634, near rs2519093) increased early-onset stroke risk, with an OR of 1.16 (95% CI 1.11–1.21) in early-onset cases, compared with an OR of about 1.05 in late-onset stroke. The interaction tests comparing early versus late effect sizes were statistically significant, indicating a genuine difference by age of onset.

Those two ABO signals together capture most of the ABO-mediated genetic effect on early stroke, and conditional analyses suggested little additional independent signal at the ABO locus once these variants are taken into account.

Why ABO is biologically plausible

The ABO gene does more than label your red blood cells. It encodes enzymes that add sugar molecules to proteins and cell surfaces. These carbohydrate tags sit on von Willebrand factor (VWF) and factor VIII, two key clotting proteins, and vary by blood group. Non-O groups, and A1 in particular, tend to have higher circulating levels of VWF and factor VIII, which can increase the blood’s tendency to clot. That biochemical link helps explain why ABO variants associate with thrombotic diseases such as VTE and, now, with early-onset ischemic stroke.

Clues from venous clotting genetics

To test the clotting hypothesis, the investigators did two complementary analyses:

• Genetic correlation: Using LD Score Regression they found a positive genetic correlation between VTE and early-onset stroke (genetic correlation ~0.376, p ≈ 0.014), but not between VTE and late-onset stroke, suggesting shared genetic contributors to blood clotting and early stroke.
• Polygenic risk score (PRS) for VTE: They built a VTE PRS using 255 SNPs from a large prior GWAS and tested whether higher VTE PRS increased stroke risk. A 1-standard-deviation increase in the VTE PRS raised the risk of early-onset stroke by about 13% (OR 1.13, 95% CI 1.10–1.16), while the effect for late-onset stroke was smaller (OR 1.04). The difference was statistically significant, consistent with a stronger role for prothrombotic genetics in younger stroke patients.

These lines of evidence converge on the idea that prothrombotic biology, as mediated in part by ABO and other clotting pathways, contributes disproportionately to stroke in younger adults.

A glance at the numbers — blood groups in cases and controls

When the researchers translated the genetics back into serologic blood groups, early-onset stroke cases were more likely to have blood group A and less likely to have blood group O than either late-onset cases or controls: about 48.4% of early-onset cases were group A, compared with 45.2% in late-onset cases and 44.4% in controls; group O was 35.5% in early-onset cases versus 39.1% in late-onset cases and 41.1% in controls. These shifts, while not dramatic at the individual level, are meaningful at the population level and match the genetic signals.

What this does not mean — no immediate genetic test for everyone

It is important to be realistic. The effect sizes of any single common ABO variant are modest. Even though the A1-tagging variant could explain an estimated 6% of early-onset stroke cases in Europeans in the paper’s back-of-the-envelope calculation, common variants on their own are rarely decisive for a person’s fate. The scientists caution that these findings do not translate into a new clinical screening test today; instead, they highlight biological pathways to study, and they suggest places to look for larger-effect rare variants or for joint gene-environment risks that might matter clinically.

Clinical and research implications — where this could lead

• Targeted research on clotting pathways. The ABO signal points researchers toward VWF, factor VIII, E-selectin, and related molecules that influence clot formation and vessel lining function. These are plausible targets for deeper functional and rare-variant studies.
• Gene-environment interactions to test. For example, oral contraceptives, smoking, or prolonged immobilization interact with clotting biology. Future work could test whether people with higher genetic clotting propensity should be counseled differently about certain risk exposures.
• Personalized prevention for high-risk young patients. While routine genetic screening is premature, genetic information could eventually be combined with family history and clinical risk factors to tailor prevention for those at especially high risk.

Caveats and next steps

The study is the largest of its kind to date for early-onset ischemic stroke, yet it has limits the scientists acknowledge:

• Sample size for discovery still modest by GWAS standards. Even with more than 16,000 cases, power to detect many small-effect variants or variants that are rare in Europeans but common elsewhere is limited.
• Ancestry diversity could be better. About 35% of participants were non-European, but the dataset remains skewed toward European ancestry, which reduces the study’s ability to find variants specific to other populations. Expanding diversity will be important.
• Need for functional follow-up. The study identifies genetic markers that tag a biological signal, but laboratory experiments are required to pinpoint the causal variants and the molecular mechanisms that increase clotting risk.
• Subtype resolution. Stroke is heterogeneous. While ABO variants associated with several subtypes including cardioembolic and large-artery stroke, subtype-specific sample sizes were smaller, so follow-up focused on subtypes would help clarify which mechanisms operate in which clinical pictures.

Bottom line — a new window onto why young people have strokes

This large, carefully controlled genetic analysis supports a model in which prothrombotic mechanisms, shaped in part by common ABO variants and the broader polygenic tendency to form clots, play an outsized role in ischemic strokes that occur under age 60. The finding does not change clinical practice overnight, but it shifts research attention toward clotting biology and gene-environment interactions that could eventually inform prevention strategies for younger people at risk.

Further reading and data access

The study was published in the journal Neurology on August 31, 2022 and is available open access. Summary-level results can be requested from the authors and individual-level data from some contributing sites may be available through dbGaP.