Abstract
Background
Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently
co-occurring and highly heritable mental health conditions. We hypothesized that BPD
cases with an early age of onset (≤21 years old) would be particularly likely to show
genetic covariation with ADHD.
Methods
Genome-wide association study data were available for 4609 individuals with ADHD,
9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically
developing controls. We conducted a cross-disorder genome-wide association study meta-analysis
to identify whether the observed comorbidity between ADHD and BPD could be due to
shared genetic risks.
Results
We found a significant single nucleotide polymorphism–based genetic correlation between
ADHD and BPD in the full and age-restricted samples (rGfull = .64, p = 3.13 × 10–14; rGrestricted = .71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant
(prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide
significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression
quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue.
Conclusions
The single nucleotide polymorphism–based genetic correlation between ADHD and BPD
is substantial, significant, and consistent with the existence of genetic overlap
between ADHD and BPD, with potential differential genetic mechanisms involved in early
and later BPD onset.
Keywords
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References
- Molecular genetics of attention-deficit/hyperactivity disorder.Biol Psychiatry. 2005; 57: 1313-1323
- A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders.Int Rev Psychiatry. 2004; 16: 260-283
- Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.Lancet. 2013; 381: 1371-1379
- Adult ADHD and its comorbidities, with a focus on bipolar disorder.J Affect Disord. 2010; 124: 1-8
- Sex- and subtype-related differences in the comorbidity of adult ADHDs.J Atten Disord. 2016; 20: 855-866
- Attention-deficit/hyperactivity disorder.Nat Rev Dis Primers. 2015; 1: 15020
- A systematic review of rates and diagnostic validity of comorbid adult attention-deficit/hyperactivity disorder and bipolar disorder.J Clin Psychiatry. 2007; 68: 1776-1784
- A history of childhood attention-deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD.Acta Psychiatr Scand. 2009; 120: 239-246
- Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.Nat Genet. 2013; 45: 984-994
- Bipolar disorder risk alleles in children with ADHD.J Neural Transm. 2013; 120: 1611-1617
- Bipolar disorder risk alleles in adult ADHD patients.Genes Brain Behav. 2011; 10: 418-423
- Assessment of response to lithium maintenance treatment in bipolar disorder: A Consortium on Lithium Genetics (ConLiGen) report.PLoS One. 2013; 8: e65636
- Case-control genome-wide association study of attention-deficit/hyperactivity disorder.J Am Acad Child Adolesc Psychiatry. 2010; 49: 906-920
- Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.Nat Genet. 2011; 43: 977-983
- LD score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat Genet. 2015; 47: 291-295
- PLINK: A tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet. 2007; 81: 559-575
- PolymiRTS Database 3.0: Linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways.Nucleic Acids Res. 2014; 42: D86-D91
- Transcriptome and genome sequencing uncovers functional variation in humans.Nature. 2013; 501: 506-511
- MatInspector and beyond: promoter analysis based on transcription factor binding sites.Bioinformatics. 2005; 21: 2933-2942
- The genetics of pediatric-onset bipolar disorder.Biol Psychiatry. 2003; 53: 970-977
- Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells.Nature. 2014; 515: 143-146
- A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23.Hum Mol Genet. 2012; 21: 456-462
- Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk.Circulation. 2013; 127: 1377-1385
- Common variants at ten loci influence QT interval duration in the QTGEN Study.Nat Genet. 2009; 41: 399-406
- The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells.Cell Signal. 2005; 17: 1343-1351
- Identification of pathways for bipolar disorder: A meta-analysis.JAMA Psychiatry. 2014; 71: 657-664
- Rare genomic variants link bipolar disorder with anxiety disorders to CREB-regulated intracellular signaling pathways.Front Psychiatry. 2013; 4: 154
- Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.Mol Psychiatry. 2014; 19: 452-461
- Genome-wide association study reveals two new risk loci for bipolar disorder.Nat Commun. 2014; 5: 3339
- Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice.Neuron. 2010; 66: 908-920
- Impaired locomotion and dopamine signaling in retinoid receptor mutant mice.Science. 1998; 279: 863-867
- Complex trait analysis of the hippocampus: Mapping and biometric analysis of two novel gene loci with specific effects on hippocampal structure in mice.J Neurosci. 2001; 21: 3503-3514
- Genome-wide association study of personality traits in bipolar patients.Psychiatr Genet. 2011; 21: 190-194
- Sex- and subtype-related differences of personality disorders (Axis II) and personality traits in persistent ADHD.J Atten Disord. 2014; 20: 1056-1065
- Genetic overlap between autism, schizophrenia and bipolar disorder.Genome Med. 2009; 1: 102
- Human HAD phosphatases: Structure, mechanism, and roles in health and disease.FEBS J. 2013; 280: 549-571
- Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm.Am J Med Genet B Neuropsychiatr Genet. 2013; 162B: 898-906
- Exome chip analyses in adult attention deficit hyperactivity disorder.Transl Psychiatry. 2016; 6: e923
- Borderline personality disorder and childhood maltreatment: A genome-wide methylation analysis.Genes Brain Behav. 2015; 14: 177-188
- Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder.Mol Psychiatry. 2015; 20: 573-584
- Polymorphisms in ABLIM1 are associated with personality traits and alcohol dependence.J Mol Neurosci. 2012; 46: 265-271
Article info
Publication history
Published online: October 18, 2016
Accepted:
August 8,
2016
Received in revised form:
July 11,
2016
Received:
April 8,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2016.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Timely Research in Bipolar Disorder and Attention-Deficit/Hyperactivity DisorderBiological PsychiatryVol. 82Issue 9
- PreviewTwo “timely” articles in this issue of Biological Psychiatry provide novel evidence for cognitive, neural, and genetic mechanisms that may underlie attentional disturbances in bipolar disorder (BD) and that directly or indirectly may help to clarify their overlap with those of attention-deficit/hyperactivity disorder (ADHD). The challenges of differential diagnosis between BD and ADHD, especially in youth, have drawn considerable focus, not least because the symptomatic expression of attentional deficits, such as distractibility, appear in both disorders within current nosological frameworks.
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