Abstract
Background
Attention-deficit hyperactivity disorder (ADHD) is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder and ADHD is aetiologically distinct from the pure disorders.Aims
To clarify whether ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia.Method
By linking longitudinal Swedish national registers, we identified 61 187 persons with ADHD (the proband group) and their first- and second-degree relatives, and matched them with a control group of people without ADHD and their corresponding relatives. Conditional logistic regression was used to determine the risks of bipolar disorder and schizophrenia in the relatives of the two groups.Results
First-degree relatives of the ADHD proband group were at increased risk of both bipolar disorder (odds ratio (OR) = 1.84-2.54 for parents, offspring and full siblings) and schizophrenia (OR = 1.71-2.22 for parents, offspring and full siblings). The risks of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full siblings.Conclusions
These findings suggest that the co-occurrence of ADHD and bipolar disorder as well as ADHD and schizophrenia is due to shared genetic factors, rather than representing completely aetiologically distinct subsyndromes.Free full text
Does attention deficit hyperactivity disorder share etiologic factors with bipolar disorder and schizophrenia?
Abstract
BACKGROUND
ADHD is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder/ADHD is etiologically distinct from the pure disorders.
AIM
To clarify if ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia.
METHODS
By linking longitudinal Swedish national registers, we identified 61,187 ADHD probands and their first and second-degree relatives and matched them with non-ADHD controls and their corresponding relatives. Conditional logistic regression was used to determine risks for bipolar disorder and schizophrenia in relatives of probands vs. controls.
RESULTS
First-degree relatives of ADHD probands were at increased risk of both bipolar disorder (ORs from 1.84 to 2.54 for parents, offspring and full siblings) and schizophrenia (ORs from 1.71 to 2.22 for parents, offspring and full siblings). The risk of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full-siblings.
CONCLUSIONS
These findings suggest that co-occurring ADHD and bipolar disorder and ADHD plus schizophrenia are due to shared genetic factors, rather than representing completely etiologically distinct sub-syndromes.
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia are highly heritable psychiatric disorders that sometimes co-occur (1–3). The extent to which ADHD shares etiologic factors with bipolar disorder and/or schizophrenia has important implications for both clinicians and researchers. Although recent studies have found shared genetic susceptibility loci as well as genetic deletions and duplications (i.e., Copy Number Variants, CNV) that overlap between these disorders (4, 5), no adequately sized family study has explored the extent to which ADHD shares familial risk factors with bipolar disorder and schizophrenia. Hence, we aimed to explore the extent to which ADHD share genetic and environmental risk factors with bipolar disorder and schizophrenia. To this end, we conducted a total population study in Sweden of ADHD probands (N=61,187) and controls. We estimated the occurrence of bipolar disorder and schizophrenia not only in ADHD probands and controls, but also in relatives to ADHD probands and controls.
METHODS
National registers
This study was based on data from Swedish longitudinal national registers held by the National Board of Health and Welfare and Statistics Sweden and linked through each individual’s unique personal identification number.
The Patient Register (administered by the National Board of Health and Welfare) has nationwide coverage for psychiatric inpatient care since 1973 and psychiatric outpatient care since 2001. Every record has a discharge date, a primary discharge diagnosis, and secondary diagnoses assigned by the treating medical doctor according to WHO’s International Classification of Diseases (ICD), based on ICD-8 for 1969-1986, ICD-9 for 1987-1996 and ICD-10 from 1997.
The Swedish Prescribed Drug Register is a national healthcare register (also administered by the National Board of Health and Welfare) with data on dispensed pharmaceuticals. Information regarding drug identity according to the Anatomical Therapeutic Chemical (ATC) classification system (ATC-code), quantity and dosage of the prescribed drug, and date of prescription/dispense has been registered since July 2005 along with specific patient information (sex, age, and area of living). The register covers the entire population of Sweden, and the identity of the patients is available for > 99.7% of the population (6).
From the Total Population Register, we obtained information on sex, birth year, and migrant status for the entire Swedish population. At the time of the construction of our database, this register covered all persons born up to 2009 and all migration events during 1969–2009. Information on vital status via death date was taken from the Swedish Cause of Death Register. At the time of the analyses, this register covered almost all deaths during 1952-2009. The Multi-Generation Register includes the personal identification numbers of index persons and their biological and adoptive parents and was used to identify parents, children, full siblings, and half siblings of index persons. At the time of the analyses, index persons were individuals born during 1932–2009 and registered in Sweden at any time period during 1961–2009 or who emigrated here together with one or both parents and obtained permanent citizenship before age 18.
Classifications of ADHD
Patients obtaining a diagnosis of ADHD between 1987 and 2009 were identified in the patient register (ICD-9: 314; ICD-10: F90). All psychiatric discharges were included and no distinction was made between primary and secondary diagnoses. Patients treated with stimulant or non-stimulant medication for ADHD (methylphenidate [N06BA04]; atomoxetin [N06BA09]; amphetamine [N06BA01]; dexamphetamine [N06BA02]) at any time between July 2005 and December 2009 were identified via the Prescribed Drug Register and also counted as ADHD probands. In the current study, patients aged 3–65 years at the time of the first ADHD diagnosis (or first prescription of stimulant or non-stimulant medication for ADHD) were included as probands.
National guidelines for medication of ADHD, issued by the Swedish National Board of Health and Welfare in 2002, states that medication should be reserved for cases where other supportive interventions have failed. This indicates that individuals with ADHD drug prescriptions represent the more severe cases of ADHD. The authority to prescribe ADHD drugs in Sweden is restricted to specialist physicians familiar with the treatment of this disorder.
We used psychiatric symptom data of 20,000 twins (born 1992–2001) from the Swedish Twin Register to explore the validity of the register-based ADHD diagnosis. ADHD symptoms in twins were assessed using the Autism – Tics, ADHD, and other Comorbidities inventory (A-TAC), which covers 96 specific child psychiatric symptoms. Two studies with extensive psychometric analyses found excellent validity for the A-TAC ADHD-measures (7). The mean ADHD score of the twins with our register-based definition of ADHD (m=9.05, SD=5.32) was substantially higher (Cohen's d=1.74) than in the total sample (m=1.73, SD=2.68). In addition, about 70% of the twins with an ADHD diagnosis were screen-positive for parent-rated ADHD. Very similar results were obtained when these validity checks were restricted to either ADHD cases identified through ICD diagnoses (i.e., Patient Register) or pharmacological ADHD treatments (i.e., Prescribed Drug Register).
Classification of Bipolar disorder and Schizophrenia
Bipolar disorder was defined as at least one discharge diagnosis (ICD-8: 296.1, 296.3, 296.8; ICD-9: 296A/C/D/E/W; ICD-10: F30-F31). Individuals with bipolar disorder who had ever been diagnosed with schizoaffective disorder (ICD-8: 295.7; ICD-9: 295H; ICD-10: F25) or schizophrenia (see below) during 1973-2009 were excluded. Similarly, we defined schizophrenia as at least one schizophrenia diagnosis (ICD-8: 295.0-295.4, 295.6, 295.8-295.9; ICD-9: 295A-295E, 295G, 295W, 295X; ICD-10: F20). Individuals with schizophrenia who also had a diagnosis of bipolar disorder or schizoaffective disorder (for criteria, see above) during 1973–2009 were excluded. All psychiatric discharges were included in this study and no distinction was made between primary and secondary diagnoses.
Statistical analysis
The statistical analyses were performed using nested case-control designs. First, we explored the associations between ADHD and bipolar disorder or schizophrenia, by comparing ADHD probands with controls. Second, we explored the familial overlap between ADHD and bipolar disorder or schizophrenia, by we compared relatives of ADHD probands with relatives of controls (parents, offspring, full siblings, maternal- and paternal half-siblings).
Probands vs. controls
We initially compared the risk for bipolar disorder and schizophrenia in probands affected by ADHD to matched controls. For each case, we randomly selected 10 control subjects matched by birth year and gender. In line with well-established procedures for nested case-control designs (3, 8), controls were alive and living in Sweden and not diagnosed with ADHD at the time of the first ADHD diagnosis of the proband.
Relatives of probands vs. relatives of controls
A family design was used to study the genetic and environmental sources of overlap between the disorders. We compared the risk for bipolar disorder and schizophrenia in relatives of probands with ADHD to relatives of matched controls. To each proband-relative pair, 10 randomly selected control-relative pairs were matched by birth year and gender of both proband and relative. This method avoids bias because of individuals in the population registries entering the study at different time points (i.e., left truncation) and allows equal follow-up periods of probands, controls and their relatives (3).
To specifically study the effect of shared genetic and environmental factors, we adjusted for the potential existence of etiologically distinct sub-syndromes (e.g., an “ADHD plus bipolar disorder” subtype), by excluding probands and controls with schizophrenia or bipolar disorder, as well as relatives to probands or controls with ADHD. Shared familial (genetic and environmental) risk factors are indicated when probands with only the index disorder have relatives with the comorbid disorders (excluding those also with the index disorder) (9). We analysed first-degree and second-degree relatives separately to assess if the observed familial association was due to genetic and/or shared environmental influences. This set of analyses were based on the following assumptions: first-degree relatives (i.e., who share 50% of their co-segregating genes) are more similar genetically than second-degree relatives (i.e., who share 25% of their segregating genes), and maternal half-siblings are more similar with regard to shared environmental exposures than paternal half-siblings because children continue to live predominantly with their mother upon parental separation (3).
To describe associations, we used odds ratios (ORs) with 95% confidence intervals (95% CIs) obtained from conditional logistic regression models in PROC PHREG in SAS version 9.3 . When studying associations within families, confidence intervals were obtained with a robust sandwich estimator function to adjust for non-independence (PROC PHREG, covsandwich option).
RESULTS
In total, we identified 61,187 individuals (41,603 males [68%]) with an ADHD diagnosis.
Risk for bipolar disorder and schizophrenia in ADHD probands
Among ADHD probands without schizophrenia (N=60,655), 4.9% had a co-occurring bipolar disorder diagnosis. In contrast, 0.2% of the controls had a bipolar disorder diagnosis. Hence, ADHD probands had a 24 times higher odds of being diagnosed with bipolar disorder compared to controls (Table 1).
Table 1
Risk for bipolar disorder and schizophrenia in probands affected by ADHD and controls matched on birth year and gender.
| Bipolar disorder | Schizophrenia | |||||
|---|---|---|---|---|---|---|
| Cases N (%) | Controls N (%) | OR (95% CI) | Cases N (%) | Controls N (%) | OR (95% CI) | |
| ADHD probandsa vs. controls | 2989 (4.9) | 1363 (0.2) | 24.0 (22.5–25.7) | 467 (0.8) | 715 (0.1) | 6.7 (5.9–7.5) |
Note:
Among ADHD probands without bipolar (N=58,133), 0.8% were also diagnosed with schizophrenia compared to 0.1% of the controls; corresponding to a substantially (OR=6.69) increased risk of a schizophrenia (Table 1).
Bipolar disorder and schizophrenia in relatives of ADHD probands
First-degree relatives of ADHD probands were more likely to have been diagnosed with bipolar disorder than first-degree relatives of controls (Table 2; ORs from 1.84 to 2.54), supporting familial influences for the overlap between ADHD and bipolar disorder. Second-degree relatives to ADHD probands were also more likely to have been diagnosed with bipolar disorder than the relatives of controls. The risk of bipolar disorder was statistically significant and similar in magnitude among maternal (OR=1.26) and paternal (OR=1.34) half-siblings, but substantially lower than for full siblings.
Table 2
Risk for bipolar disorder and schizophrenia in relatives to probands with ADHD and controls matched on birth year and gender.
| Bipolar disorder in relatives | Schizophrenia in relatives | |||||
|---|---|---|---|---|---|---|
| Probands N (%) | Controls N (%) | OR (95% CI) | Probands N (%) | Controls N (%) | OR (95% CI) | |
| First-degree relatives | ||||||
| Parents | 986 (0.95) | 4835 (0.51) | 1.84 (1.72–1.97) | 366 (0.35) | 1503 (0.16) | 2.22 (1.99–2.47) |
| Offspring | 52 (0.28) | 187 (0.12) | 2.54 (1.92–3.35) | 15 (0.08) | 75 (0.05) | 1.89 (1.13–3.15) |
| Full siblings | 319 (0.52) | 1212 (0.23) | 2.22 (1.98–2.50) | 142 (0.23) | 676 (0.13) | 1.71 (1.44–2.04) |
| Second-degree relatives | ||||||
| Maternal half-siblings | 88 (0.44) | 135 (0.32) | 1.26 (1.01–1.58) | 33 (0.17) | 54 (0.13) | 1.11 (0.78–1.58) |
| Paternal half-siblings | 84 (0.38) | 132 (0.29) | 1.34 (1.06–1.71) | 44 (0.20) | 73 (0.16) | 1.06 (0.79–1.43) |
Further, first-degree relatives to probands with ADHD were more likely to have schizophrenia than relatives to controls (Table 2; ORs from 1.71 to 2.22). The risk of schizophrenia was similar among maternal (OR=1.11) and paternal (OR=1.06) half-siblings and substantially lower than for full siblings.
DISCUSSION
We conducted a large-scale nationwide family study to clarify if ADHD shares genetic and environmental risk factors with bipolar disorder and schizophrenia. The results showed an increased risk of both bipolar disorder and schizophrenia in relatives of ADHD probands (N=58,133–60,655). Moreover, the risks among half-siblings were considerably lower than in full siblings, and but similar in maternal and paternal half-siblings. These familial aggregation patterns indicate that these disorders share genetic factors, rather than environmental factors, which is consistent with prior twin study results for ADHD (10), bipolar disorder (11), and schizophrenia (12), suggesting substantial heritability and a limited role of shared environmental effects.
Prior family studies of ADHD and bipolar disorder indicate that relatives of ADHD probands with co-occurring bipolar disorder have increased risk of bipolar disorder, but not relatives to probands with ADHD only (13, 14). One interpretation of those results is that the two disorders are transmitted together in families reflecting a familially distinct syndrome. By contrast, however, we found that pure ADHD in probands actually predicted pure bipolar disorder in relatives. A potential explanation to these conflicting results is that the previous studies were underpowered regarding the detection of a familial association between pure ADHD and bipolar disorder. Our results, thus, indicate that shared etiologic factors rather than a etiologically distinct ADHD plus bipolar disorder subtype explains the observed overlap between ADHD and bipolar disorder. However, the finding that the overlap between ADHD and bipolar disorder is due to shared genetic factors does not exclude that “ADHD plus bipolar disorder” might differ pathophysiologically from the pure forms of the respective disorders (13, 14). Nor does it exclude specific etiologic factors for the respective disorder.
The comorbidity of ADHD and schizophrenia has received less attention in prior research and no study has addressed the occurrence of schizophrenia in relatives of ADHD probands. Our results extend prior findings of comorbid ADHD in childhood onset schizophrenia (84% prevalence) (15), and also results from high-risk studies suggesting that ADHD is overrepresented in offspring to schizophrenia probands (20–35% prevalence) (16, 17).
Altogether and in line with previous research (18, 19), we found a higher risk of co-occurring bipolar disorder than schizophrenia in individuals with ADHD, which might at least partly reflect the fact that ADHD shares more symptoms with bipolar disorder than with schizophrenia (20). In contrast, the familial aggregation patterns of bipolar disorder were very similar to that of schizophrenia. These results are not consistent with the idea of an etiologically distinct ADHD plus bipolar disorder subtype, and may instead suggest pleiotropic genetic effects across these disorders. Such an interpretation is in line with recent CNV findings suggesting genetic overlaps between ADHD, autism and schizophrenia (4, 5), and the well-established neurocognitive overlap between ADHD, bipolar disorder and schizophrenia (21–23), perhaps reflecting a broader liability to neurodevelopmental impairment that also includes autism spectrum disorders and intellectual disability (24); even though recent studies of copy number variants reminds us that disorder specific variants also are involved (25). Our findings lend support to comparative studies investigating genetic and neurocognitive factors common across these disorders.
Strengths and limitations
The main strength of this study was our ability to address the risk of bipolar disorder and schizophrenia primarily in first-degree and second-degree relatives of pure ADHD probands and controls. Second, this study was powered to yield robust, unambiguous results. One potential limitation is that the outpatient register is relatively new (started in 2001). These data, thus, should not be used for prevalence estimates as some of the study participants may have been diagnosed prior to register follow-up or may still be at risk at the end of follow-up. This potential bias does not influence the observed associations between ADHD and bipolar disorder or schizophrenia as the nested case-control method allows equal follow-up periods of probands, controls and their relatives. Another limitation is the non-standardized register diagnoses. However, validity studies of bipolar disorder (26) and schizophrenia (27), as well as our own validity checks of ADHD using data from the Swedish twin register support high specificity for the register-based diagnosis. Specifically, a bipolar disorder diagnosis based on the Swedish inpatient register showed 92% agreement when compared to reassessed diagnostic status based on patients medical records (26), whereas inpatient schizophrenia diagnoses indicated 94% agreement when compared to research diagnoses based on semi-structured interviews and medical records (27).
Acknowledgments
Funding: Financial support was provided through the regional agreement on medical training and clinical research (ALF 20100305) between Stockholm County Council and Karolinska Institutet; and through grants from the Swedish Medical Research Council (K2010-61X-21569-01-1, K2010-61P-21568-01-4 and 2010-3184) and National Institute of Child Health and Human Development (HD061817).
Footnotes
Declaration of interest: None.
Author contributions: All authors have contributed to and approved this manuscript. HL contributed to analysis and interpretation of data, and drafting the article. ER contributed to analysis and interpretation of data, and drafting the article. MB contributed to analysis and interpretation of data, and drafting the article. NL contributed to conception and design and revising the article critically for important intellectual content. PL contributed to conception and design and revising the article critically for important intellectual content. ML contributed to conception and design and revising the article critically for important intellectual content.
REFERENCES
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Funding
Funders who supported this work.
NICHD NIH HHS (2)
Grant ID: HD061817
Grant ID: R01 HD061817
