One of the clearest demonstrations of a rule that governs all of this: the more people they looked at, the smaller the effect got. It started at 1.31 and finished at 1.17 — and the second number is the honest one.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Bipolar disorder is a psychiatric illness of episodes — sustained periods of elevated mood and energy alternating with depression. It is among the most heritable common conditions in medicine: twin studies put it far above diabetes or heart disease.
Which makes what happened to this variant instructive.
A 2011 study followed a single position through three progressively larger samples.
The association is real; it survived a replication ten times the size of the discovery. But the effect fell by nearly half between the first look and the second.
It has a name — the winner's curse — and it is a property of how discovery works rather than a fault in this study.
A variant is flagged because it crossed a threshold in one sample. Crossing a threshold takes a real effect plus, usually, a bit of luck. The real effect stays when you look again; the luck does not. So first estimates are biased upward, and it is the replication that tells you the size.
Anyone reading genetic findings should expect this. A striking odds ratio in a first report is a starting number, not a measurement.
NCAN encodes neurocan, a glycoprotein in the extracellular matrix — the scaffolding between brain cells rather than a neurotransmitter or a receptor. It is involved in cell adhesion and migration, and in mice its expression is concentrated in cortical and hippocampal areas.
Those are regions independently implicated in bipolar disorder by imaging and neuropsychology, which is the sort of convergence that makes a statistical finding more believable.
These two facts sit together and confuse people, so it is worth stating plainly.
Bipolar disorder runs in families strongly. It is also polygenic to an extreme degree: the inheritance is spread across a very large number of positions, each contributing an odds ratio near 1.1. An odds ratio of 1.17 against a population risk of around 1 percent moves an individual almost not at all.
Heritable does not mean predictable from any one position, and this is the condition that shows it most clearly.
Mullins et al. 2021, the Psychiatric Genomics Consortium, compared 41,917 people with bipolar disorder against 371,549 controls, all of European ancestry, and found 64 associated loci. The risk alleles were concentrated in genes for synaptic signalling and in genes expressed in the brain — particularly in neurons of the prefrontal cortex and hippocampus, the same regions the NCAN story above pointed at. They were also enriched in genes encoding the targets of antipsychotics, calcium channel blockers, antiepileptics and anaesthetics, and gene-expression data implicated 15 genes including HTR6, MCHR1, DCLK3 and FURIN. Bipolar I and bipolar II were highly but imperfectly correlated genetically, and analysing the subtypes separately found additional loci.
15 of this page's variants come from that bipolar I analysis. Three of them sit in calcium-channel genes — CACNA1C, CACNB2 and CACNA1B — which is the calcium-channel-blocker finding seen from the variant side; and rs112219496 is in NCAN, the gene of the 2011 study, ten years and forty thousand patients later. Each still carries an odds ratio near 1.1; the number that changed is how many of them there are.
Bipolar disorder is diagnosed by a clinician from a history of episodes over time — which is difficult, often delayed, and not something a genotype accelerates. No variant here is used in diagnosis, in prognosis, or in choosing between lithium, anticonvulsants and antipsychotics.
If any of this is a live question for you or someone close to you, the useful move is a psychiatric assessment. It is the only thing on this page that changes an outcome.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 54 more positions to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Mullins N et al. 2021, Nature genetics rs112481526 (BLTP1), rs28455634 (C16orf72), rs12672003 (MPP6), rs35306827 (CUL4A), rs2336147 (ITIH1), rs10866641 (DOCK2), rs67712855 (WFDC12), rs748455 (ZNF592), rs10917509 (HTR6), rs28565152 (ADCY2), rs237460 (KCNB1), rs2953928 (RP1-84O15.2 (lincRNA)) and 5 more — PMID:34002096
Verma A et al. 2024, Science (New York, N.Y.) rs973359197 (SERTAD2), rs534919791 (near ATP11AUN), rs948462796 (WDPCP), rs183292232 (near LINC01122), rs541650762 (CCDC60), rs190958890 (MGLL), rs77817138 (near ANKRD11), rs184369225 (near DLG5-AS1), rs184489828 (near CNTN5), rs185219225 (SACS), rs529892601 (DIRC3), rs552029205 (DDX25) — PMID:39024449
Yao X et al. 2021, Translational psychiatry rs7001340 (LETM2), rs68188794 (ZSCAN16), rs9926049 (GRIN2A), rs72692857 (near OTUD7B), rs11191356 (near SUFU), rs138321 (SLC25A17), rs11648559 (GRIN2A), rs12563424 (TMEM56), rs13236223 (near CCT4P1), rs4239639 (MAU2) — PMID:33479212
Li HJ et al. 2021, JAMA psychiatry rs11647445 (GRIN2A), rs3804640 (CD47), rs6130764 (STK4), rs11557713 (ZCCHC2), rs41335055 (VRK2), rs12902052 (ZNF592) — PMID:33263727
Stahl EA et al. 2019, Nature genetics rs17183814 (SCN2A), rs10896090 (SART1), rs10035291 (RNU5E-1), rs11724116 (FSTL5) — PMID:31043756
Hou L et al. 2016, Lancet (London, England) rs74795342 (AL157359.3), rs78015114 (AL157359.3) — PMID:26806518
Pisanu C et al. 2019, Translational psychiatry rs4141973 (near FTH1P5) — PMID:31754094
Choi MJ et al. 2026, Asian journal of psychiatry rs75776799 (SLC25A12) — PMID:42229218
Ho AM et al. 2020, Clinical pharmacology and therapeutics rs78835388 (THSD7A) — PMID:32627186
2026-06-01 · Genome-wide association study and polygenic risk score analysis for bipolar disorder in the Korean population. Asian Journal of Psychiatry. 2026. PMID:42229218
First Korean bipolar disorder GWAS finds a mitochondrial-transporter gene also tied to autism
Most bipolar disorder GWAS data comes from European-ancestry cohorts. This study, run through the Korean Psychiatric GWAS Project across seven academic institutions, analyzed 1,538 Korean adults with bipolar I or II disorder against 2,271 controls and found one genome-wide significant locus: rs75776799, an intronic variant in SLC25A12 (P=2.45x10^-9, OR=2.65, 95% CI 1.92-3.64, effect allele frequency 0.0398 -- a low-frequency variant with a comparatively large effect). SLC25A12 encodes a mitochondrial aspartate/glutamate carrier and has previously been implicated in autism spectrum disorder, suggesting a possible shared role for mitochondrial function across these conditions. A separate Mendelian randomization analysis using East Asian methylation QTL data found suggestive links to DLX2-AS1 and ITGA6, and polygenic risk scores built from multi-ancestry (rather than single-ancestry) GWAS data explained the most variance in this Korean sample -- a practical finding for how genetic risk tools should be built for non-European populations. This site's bipolar disorder page carries 22 variants; rs75776799/SLC25A12 is a genuinely new locus not currently among them. It is confirmed in GWAS Catalog (accession GCST90860954, matching this paper exactly), but the underlying Variant row has not yet been created by this site's standard GWAS Catalog collection pipeline, so this entry documents the finding at the condition level rather than hand-adding an unverified variant page outside that pipeline.
2025-12-10 · Nature
A study analyzing genetic data from over 1 million cases across 14 psychiatric disorders together, rather than one at a time, found five latent genetic factors explaining about 66% of the genetic variance in the individual disorders, plus 238 loci with effects that cross disorder boundaries. Schizophrenia and bipolar disorder formed one such factor, sharing so much of their genetic signal that the study found very few loci specific to either disorder alone -- that shared factor was linked to gene expression specifically in excitatory neurons. A separate factor grouped major depression, PTSD and anxiety, linked instead to oligodendrocyte biology. The authors frame this as evidence for regrouping psychiatric diagnosis around shared underlying biology rather than the current symptom-based categories. PMID:41372416.
The source. Cichon et al. (Am J Hum Genet 2011) investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with bipolar disorder and 1,300 controls, tested the 48 most significant SNPs in 1,729 patients and 2,313 controls, and meta-analysed. rs1064395 in NCAN reached genome-wide significance in 2,411 patients and 3,613 controls (p = 3.02 × 10⁻⁸, OR 1.31). A second follow-up in independent samples totalling 6,030 patients and 31,749 controls replicated the finding (p = 2.74 × 10⁻⁴, OR 1.12); combined analysis gave p = 2.14 × 10⁻⁹, OR 1.17.
Effect size and the winner's curse. The decline from 1.31 to 1.12 between discovery and independent replication is the expected consequence of selecting a variant on its having exceeded a significance threshold in a finite sample: the estimate at discovery captures both the true effect and the sampling deviation that helped it cross. The combined OR of 1.17 remains the better estimate, and it is the one to quote.
NCAN. Neurocan is a chondroitin sulphate proteoglycan of the extracellular matrix implicated in cell adhesion and migration. The authors reported murine expression localised to cortical and hippocampal areas, regions previously implicated in bipolar disorder through neuropsychological, neuroimaging and post-mortem work.
Architecture. Bipolar disorder has among the highest twin-study heritability estimates of any common disorder while individual common variants carry odds ratios near 1.1, which is the signature of an extremely polygenic architecture. Polygenic scores for bipolar disorder discriminate at the group level and are not clinically actionable for an individual.
Clinical boundary. Diagnosis is clinical, resting on the longitudinal course of mood episodes, and is frequently delayed by years. No genotype contributes to diagnosis, to prediction of course, or to the selection of mood stabilisers or antipsychotics.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Bipolar Disorder comes down to these specific, well-studied positions — not a diagnosis. 94 positions are linked to this page; the ones this page's own text discusses are shown first.
ADM · rs6484218
See detailed info →ANK3 · rs10994359
See detailed info →HLA · rs209474
See detailed info →MEF2C · rs324899
See detailed info →CMAHP · rs6942227
See detailed info →TAF9BP2 · rs7089973
See detailed info →The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 29 of 94 linked studies with a resolved discovery ancestry.
Free to quote and reuse under CC BY 4.0. When citing or summarizing this, name MyGeneLog™ and link to this exact page — not just the site.
Bipolar Disorder. MyGeneLog™. https://www.mygenelog.com/conditions/bipolar-disorder
Because the first number included luck and the second did not. A variant gets flagged for crossing a threshold, and crossing takes a real effect plus, usually, a favourable sample. The effect stays when you look again; the luck does not. It is called the winner's curse and it happens to nearly every first report. The combined 1.17 is the number to quote.
Because the inheritance is spread very thin. A great many positions each add a little, and no single one carries much. Heritable and predictable-from-one-position are different claims, and bipolar disorder is the clearest case of the gap between them.
No. It is diagnosed from the course of mood episodes over time, by a clinician. Diagnosis is often delayed by years, which is a real problem, and no genotype shortens it. An assessment does.
It is less strange than it looks. Neurocan sits in the matrix between brain cells and is involved in how they adhere and migrate, and in mice its expression concentrates in cortical and hippocampal regions — the same regions imaging and neuropsychology had already implicated.
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.