Evidence map›Paper›PMID 33729739›Full record

ArticleJournal of psychiatry & neuroscience : JPN2021

A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21.

Claudio Toma, Alex D Shaw, Anna Heath, Kerrie D Pierce, Philip B Mitchell, Peter R Schofield, Janice M Fullerton

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of psychiatry & neuroscience : JPN, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.2field-weighted citation impact, top 20% of its field
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

6 citing papers in PubMed, 9 citations in OpenAlex.

  1. Rare Homozygous Variants inInternational journal of molecular sciences · 2025
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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

7 authors at 6 institutions in 2 countries.

Claudio TomaFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
Alex D ShawFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
Anna HeathFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
Kerrie D PierceFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
Philip B MitchellFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
Peter R SchofieldFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
Janice M FullertonFrom Neuroscience Research Australia, Sydney, Australia (Toma, Shaw, Heath, Pierce, Schofield); the School of Medical Sciences, University of New South Wales, Sydney, Australia (Toma, Shaw, Schofield, Fullerton); the Centro de Biología Molecular 'Severo Ochoa', Universidad Autónoma de Madrid/CSIC, Madrid, Spain (Toma); the School of Psychiatry, University of New South Wales, Sydney, Australia (Mitchell); and the Black Dog Institute, Prince of Wales Hospital, Sydney, Australia (Mitchell).
University of Sydney · AUBlack Dog Institute · AUCentro de Biología Molecular Severo Ochoa · ESNeuroscience Research Australia · AUPrince of Wales Hospital · AUUNSW Sydney · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Background: Bipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness. Methods: Overall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder-manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a genebased segregation test. Results: We identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LODexp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies - or variants in linkage disequilibrium with those variants - did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014). Limitations: We did not examine non-coding variants, but they may explain the remaining linkage signal. Conclusion: Combining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.

Indexed as

AllelesGenetic LinkageGenetic Predisposition to DiseaseAnkyrinsBipolar DisorderChromosomes, Human, Pair 10ExomeExome SequencingFemaleGenome-Wide Association StudyHumansMalePolymorphism, Single NucleotideANK3 protein, humanAnkyrins

Identifiers

PMID33729739
PMCPMC8061732
OpenAlexW3136384553

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

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 OpenQuestion graph.