The Only Gene Linked to Neuroticism in 63,661 People Failed to Replicate
A large personality genetics study found one genome-wide significant variant — and then could not confirm it in an independent sample. What survived is more interesting than the headline hit.
A questionnaire asks whether you often feel tense, whether you worry, whether your mood shifts easily. You tick boxes. Sixty-three thousand other people tick the same boxes.
That is the raw material of personality genetics, and it is what the Genetics of Personality Consortium pooled across 30 cohorts — 63,661 participants in the discovery analysis, plus an independent replication sample of 9,786 (de Moor et al., JAMA Psychiatry, 2015, PMID: 25993607).
They found one. rs35855737, in the gene MAGI1 on chromosome 3, at p = 9.26 × 10⁻⁹.
Then they tried to replicate it, and it did not replicate. In the independent sample, p = 0.32.
Why the paper reported that anyway
This is the part worth admiring. The finding survived a meta-analysis across all 30 cohorts at p = 2.38 × 10⁻⁸ — still genome-wide significant — and the authors published the failed replication alongside the hit rather than quietly resting on the combined figure.
That is what a well-behaved result looks like when it is uncertain. Most single-variant findings for personality traits have gone the same way. The honest position is that no individual variant has a large, reliably reproducible effect on neuroticism.
What did hold up
Two things, and they are the substance of the paper.
Common genetic variants explain about 15% of the variance in neuroticism. Not one gene — the aggregate of many common variants across the genome. Real, measurable, and far below the ~40% that twin studies typically report for personality traits.
Polygenic scores predicted both neuroticism and major depressive disorder in cohorts not used to build them. The same genetic signal that tracks the personality trait also tracks depression risk, supporting a shared biological basis between the two.
MAGI1 itself is not a random gene, either — it had previously been associated with bipolar disorder and schizophrenia, which is consistent with the overlap the polygenic analysis found.
Reading a personality result honestly
Neuroticism is measured by questionnaire. It is a stable, well-validated psychological construct, and it is also a self-report, sensitive to mood on the day, culture, and how a person interprets the questions.
A genetic score for such a trait is a statistical position, several steps removed from anything you would recognise as a personality. It says nothing about whether someone is anxious, resilient, difficult or calm, and it predicts nothing about how any individual will respond to any particular thing that happens to them.
What the app reports
The Neuroticism App applies findings from this line of research to your genotype and shows where you would have fallen among the study participants had you taken part in it.
That framing matters more here than almost anywhere else. A personality score is not a description of your character — it is a position in someone else's dataset, on a trait measured by questionnaire, from variants that individually explain almost nothing.