Findings in the context of previous work

These findings are consistent with the recent twin study by Higier and colleagues ^{Reference Higier, Jimenez, Hultman, Borg, Roman and Kizling12} which found that supra-normal levels of verbal proficiency might represent a trait marker for bipolar disorder and they are in line with the work by Gale and colleagues ^{Reference Gale, Batty, McIntosh, Porteous, Deary and Rasmussen16} who suggested that high intelligence may be a risk factor for ‘pure’ or ‘non-comorbid’ bipolar disorder in men. Although MacCabe and colleagues ^{Reference MacCabe, Lambe, Cnattingius, Sham, David and Reichenberg14} looked at the association between educational attainment (rather than IQ) and later risk of bipolar disorder, they found a positive association for men (but not for women). It is notable that, as with Higier and colleagues’ twin study, we found that the association between IQ and later features of bipolar disorder applied to both men and women. We did not find that lower childhood IQ predicted manic features in adulthood.

More broadly, our finding that higher IQ scores (particularly VIQ) measured in childhood were associated with higher scores on a dimensional measure of lifetime manic features assessed in early adulthood is also consistent with research suggesting that the genetic propensity to bipolar disorder may be associated with a range of creative abilities, especially in areas where verbal proficiency may prove advantageous to the individual, such as in literature or in leadership roles. ^{Reference Richards, Kinney, Lunde, Benet and Merzel2,Reference Murray and Johnson5,Reference Santosa, Strong, Nowakowska, Wang, Rennicke and Ketter29} To some extent, this is supported by studies which have identified that the clinical states of mania and hypomania are associated with both greater combinatory thought processes ^{Reference Solovay, Shenton and Holzman30} and greater associational fluency. ^{Reference Henry, Weingartner and Murphy31–Reference Levine, Schild, Kimhi and Schreiber33}

Most neurocognitive research on bipolar disorder has found that individuals, as well as to a lesser extent their non-bipolar first-degree relatives, have subtle deficits in verbal memory, sustained attention and executive function ^{Reference Bourne, Aydemir, Balanzá-Martínez, Bora, Brissos and Cavanagh34–Reference Bora, Yucel and Pantelis36} and that these impairments are associated with functional impairment. ^{Reference Malhi, Ivanovski, Hadzi-Pavlovic, Mitchell, Vieta and Sachdev37,Reference Torres, DeFreitas, DeFreitas, Bond, Kunz and Honer38} These deficits may also get worse over time with repeated episodes of illness. ^{Reference Gildengers, Mulsant, Begley, Mazumdar, Hyams and Reynolds Iii39,Reference Moorhead, McKirdy, Sussmann, Hall, Lawrie and Johnstone40} In this regard, it could be considered surprising that we did not find an association between lower childhood IQ and manic features in young adulthood. However, the neurodevelopmental trajectory of bipolar disorder (in contrast to schizophrenia) is not characterised by significant motor delays and cognitive difficulties in childhood, with many individuals who later go on to develop bipolar disorder performing at least as well as the general population ^{Reference Demjaha, MacCabe and Murray41} (although bipolar disorder with an onset in childhood may have a neurodevelopmental profile which is closer to that of schizophrenia). ^{Reference Arango, Fraguas and Parellada42} It is therefore possible that our findings refer to a group of young adults in the early or prodromal stages of bipolar disorder, a proportion of whom may not ultimately go on to develop the full-blown disorder.

Strengths and limitations

The study analysed data from a large birth cohort that is representative of the UK general population in terms of ethnicity, social class and educational attainment. The assessment of childhood IQ at age 8 years, approximately 14 years before the assessment of manic features, as well as the depth of baseline data that were available for assessing the impact of confounding factors, all represent major methodological strengths.

Our primary outcome of interest was a dimensional score for lifetime manic features, derived from 28 items selected from the HCL-32 questionnaire. ^{Reference Court, Forty, Jones, Gordon-Smith, Jones and Craddock18} Clearly, as noted above, higher scores on this instrument are not diagnostic of bipolar disorder but we would argue that higher transformed scores on this measure are a good quantitative assessment of propensity to bipolar disorder, particularly in a population sample of young adults who are likely to be still below the age threshold for experiencing a first episode of mania. ^{Reference Leboyer, Henry, Paillere-Martinot and Bellivier43,Reference Hamshere, Gordon-Smith, Forty, Jones, Caesar and Fraser44} The use of dimensional measures of psychopathology in this way is consistent with a view of mental disorders as quantitative traits. ^{Reference Plomin, Haworth and Davis45} Furthermore, the dimensional nature of the modified questionnaire fits with prior research supporting a dimensional nature of vulnerability to mania. ^{Reference Meyer and Keller46} This is also in line with recent recommendations that dimensional, rather than strict categorical approaches, such as those suggested within the Research Domain Criteria, ^{Reference Cuthbert and Insel47,Reference Insel, Cuthbert, Garvey, Heinssen, Pine and Quinn48} may be more useful for understanding the aetiology of psychiatric conditions. ^{Reference Insel49} There is now good evidence that lifetime features of mania occur along a spectrum of mood and psychotic disorders that includes (but is likely not limited to) the categorical diagnoses of recurrent major depressive disorder, bipolar disorder and schizophrenia. ^{Reference Cardno and Owen50–Reference Craddock and Owen54}

Possible limitations of the HCL-32 instrument include the fact that, as a self-report measure, it may be subject to reporting biases, for example, in areas such as sexual activity, risk taking and alcohol use, where young adults might be more likely to respond affirmatively to these statements. However, this instrument has been used very widely in young adult populations and is well validated with respect to screening for bipolar disorder in clinical and young adult population settings. ^{Reference Meyer, Schrader, Ridley and Lex22} The opening statement specifically asks respondents to remember ‘a period when you were in a high state, not related to recreational drug use.’ It is still possible that scores on this questionnaire may have been related to current drug or alcohol use but unfortunately we did not have a contemporaneous measure which would allow us to take this into account within our analyses. Further, it is unlikely that drug or alcohol use would have confounded the IQ measures because they were taken at age 8 years.

Another important limitation relates to the extent to which our study sample is representative of the original ALSPAC cohort and, more broadly, the general population. It is likely that there was an attrition bias in this study. Compared with the rest of the ALSPAC cohort, our study sample had higher IQ, higher maternal social class, higher maternal education level and lower rates of maternal depression. There was also a greater proportion of females and participants of White ethnicity. This attrition represents a limitation of this study but to minimise this possibility we used multiple imputation (Table 5). Within these imputed analyses our findings were similar to the complete case analyses.

Implications

In evolutionary terms, our findings suggest that there may be some selective advantage associated with propensity to serious recurrent disorders of mood such as bipolar disorder. Higher IQ in childhood is likely to advantageous for the long-term reproductive fitness of our species but it is possible that the trade-off for this is greater liability to recurrent depression and/or bipolar disorder. Our findings open the way for more detailed genetic investigations of the relationship between intelligence and bipolar disorder (including, for example, polygenic risk score approaches), as well as assessments of the extent to which childhood IQ might represent an endophenotypic marker for later bipolar disorder. Future work should also assess the contribution of copy number variations (CNVs) to this relationship between IQ and bipolar disorder, given that large CNVs are more strongly associated with schizophrenia, autism and intellectual disability than with bipolar disorder. ^{Reference Green, Rees, Walters, Smith, Forty and Grozeva55} Finally, our findings support quite recent evidence that VIQ or verbal proficiency may represent biomarkers or endophenotypes for bipolar disorder ^{Reference Higier, Jimenez, Hultman, Borg, Roman and Kizling12} and in this regard should stimulate future work on the genetic relationship between VIQ and recurrent disorders of mood such as bipolar disorder.

In summary, this prospective study has identified that performance on childhood IQ tests at age 8 years was positively correlated across the IQ range with lifetime features of bipolar disorder experienced in early adulthood, even after adjusting for a range of confounding factors. Clinically, these findings may have implications for the development of approaches which seek to identify subgroups of adolescents and young adults who may be at higher risk of developing bipolar disorder, for example, those with exceptional verbal proficiency in the context of other known risk factors for bipolar disorder, such as high genetic loading, ^{Reference Craddock and Sklar56} exposure in utero to influenza ^{Reference Canetta, Bao, Co, Ennis, Cruz and Terajima57} or childhood trauma. ^{Reference Etain, Aas, Andreassen, Lorentzen, Dieset and Gard58}