Evidence map›Paper›PMID 42834204›Full record

ArticleNature genetics2026

A heritability-optimized method for functional prioritization of rare coding variants in complex traits.

Keona Pang, Nazia Pathan, Ann Le, Alice Man, Josef Graf, Yanran Li, Guilherme L da Rocha, Elad Shemesh, Daria Grafodatskaya, Michael R Chong and 1 more

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Article in Nature genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Keona PangPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Nazia PathanPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.ORCID http://orcid.org/0000-0002-2414-8312
Ann LeComputational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Alice ManPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.ORCID http://orcid.org/0000-0002-8011-1864
Josef GrafDepartment of Computing and Software, Faculty of Engineering, McMaster University, Hamilton, Ontario, Canada.ORCID http://orcid.org/0009-0001-5530-6790
Yanran LiPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Guilherme L da RochaPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Elad ShemeshPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Daria GrafodatskayaHamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Michael R ChongPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
Guillaume ParéPopulation Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada. pareg@mcmaster.ca.ORCID http://orcid.org/0000-0002-6795-4760

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Population sequencing studies are uncovering millions of missense rare variants (RVs) implicated in the 'missing heritability' of complex diseases, yet distinguishing functional from neutral variation remains challenging. Here we present rare variant heritability-optimized scores (RovHer), a heritability-optimized method for inferring a variant's probability of being functional (that is, its contribution to trait variance). RovHer leverages exome-wide association statistics across 4,927,334 RVs and uses multivariate adaptive regression splines to integrate 75 variant- and gene-level features without a priori constraints. Across 21 traits in up to 357,086 UK Biobank European individuals, the top 1% of RovHer-prioritized missense RVs (m = 13,410) explained, on average, 16.1% of total RV heritability, a 10-fold gain over 7 alternative methods (average 1.5%; range 1.2-2.3%). RovHer's predictions are independent of allele frequency, generalize in a multi-ancestry replication and effectively identify high-risk carriers of severe clinical outcomes across 17 monogenic gene-trait pairs. Our tool showcases the value of missense RVs in population risk stratification.

Indexed as

Genetic VariationMultifactorial InheritanceExomeGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansModels, GeneticMutation, MissensePhenotypePolymorphism, Single Nucleotide

Identifiers

PMID42834204

What Socratic holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.