Who develops heart failure, not what happens after — a study of 1.9 million people found 66 genetic loci, and that the genetics differ by cause: a blocked artery, a weakly pumping heart, and a stiffly filling one are genetically distinguishable, not one disease with three names.
Heart failure is not one disease with one cause. The heart can fail to pump enough blood because a blocked coronary artery has starved part of the heart muscle (an ischemic cause), or for reasons unrelated to blocked arteries (non-ischemic) — and even within the non-ischemic group, the heart can fail by pumping too weakly (reduced ejection fraction, HFrEF) or by pumping a normal amount but filling too stiffly between beats (preserved ejection fraction, HFpEF). This page is about a study that asked whether these differences, long recognized clinically, are also genetically distinct.
Henry, Mo, Finan et al. 2025 analysed 1.9 million people, including 153,174 with heart failure. Of those, 44,012 had a non-ischemic cause, and where clinical data allowed, this group was split further: 5,406 with reduced ejection fraction and 3,841 with preserved ejection fraction. The study found 66 genetic loci associated with heart failure and its subtypes, 37 of them newly reported.
The subtype split is the point of the study, not a side detail. Using gene-prioritization methods, the researchers mapped the loci to genes, then grouped those genes into disease clusters using three independent methods — phenome-wide association, network analysis, and colocalization — and found the clusters differed by subtype. A locus associated with the ischemic route through heart failure was not, in general, the same locus driving the non-ischemic, reduced-ejection-fraction route.
A heritability enrichment analysis — asking which tissues carry the biological signal behind these loci — found a real role for tissues outside the heart itself. Heart failure's genetic architecture is not confined to heart muscle; other organ systems contribute to why some people develop it and others do not. The study also used Mendelian randomization, a method for testing whether an already-known risk factor (like high blood pressure or obesity) actually causes a subtype of heart failure rather than merely correlating with it, and found the risk factors associated differently across the ischemic and non-ischemic subtypes.
This page is deliberately separate from heart failure progression, which covers a later, different question: among people who already have heart failure, what predicts a faster or slower disease course. This page is about who develops heart failure in the first place.
Heart failure is diagnosed clinically — by symptoms, imaging and blood tests — not by genotype. The ischemic-versus-non-ischemic and reduced-versus-preserved-ejection-fraction distinctions on this page are how the underlying research grouped its participants, based on their existing clinical diagnoses; no variant here is used to sort a person into one subtype or another.
66 loci across a condition with a heritable component estimated well below 100% means most of what determines whether any one person develops heart failure is not captured by this list — clinical risk factors (blood pressure, coronary disease, diabetes, obesity) remain the dominant, actionable levers. What this research adds is not a prediction tool but a partial map of why the disease looks different from one patient to the next at a biological level, which is a starting point for future subtype-specific treatment research, not a finished one.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Heart Failure comes down to these specific, well-studied positions — not a diagnosis. 55 positions are linked to this page; the ones this page's own text discusses are shown first.
NOL4 · rs149780392
See detailed info →HLF · rs3794752
See detailed info →near LSM3 · rs62233286
See detailed info →BAG3 · rs7095308
See detailed info →near GALNT8 · rs73048654
See detailed info →IGFBP7 · rs143445113
See detailed info →Databases, guidelines and references
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Heart Failure. MyGeneLog™. https://www.mygenelog.com/conditions/heart-failure
Not one disease. A 2025 study of 1.9 million people found that whether heart failure is caused by a blocked artery (ischemic) or not (non-ischemic), and whether a non-ischemic heart pumps too weakly or too stiffly, are associated with genetically distinguishable loci — not just different clinical presentations of the same underlying genetic risk.
No. Heart failure and its subtypes are diagnosed clinically, through symptoms, imaging and blood tests. These 66 loci explain part of the inherited risk at a population level and are a research finding about disease mechanism, not a diagnostic or predictive tool.
No — established clinical risk factors remain the dominant, actionable drivers of heart failure risk. This research maps part of the biological background behind why the disease looks different from patient to patient, not a replacement for managing those risk factors.
This page is about who develops heart failure. The progression page is about people who already have heart failure, and what predicts whether their disease stays stable or worsens sooner — a later, different question, kept on a separate page on purpose.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog™. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.