Depression, migraine with aura and migraine without aura: their familiality and interrelatedness.

Abstract

Migraine is frequently comorbid with depression. There appear to be common aetiological factors for both disorders, but the aetiology of migraine within depressed patients, in particular the significance of aura, has been little studied. A large sample of concordantly depressed sibling pairs [the Depression-Network (DeNT) sample] was assessed as having migraine with aura (MA), migraine without aura (MoA), probable migraine or no migraine according to International Headache Society guidelines. Correlations between siblings' migraine status were used to assess the nature of familial liability to migraine. A multiple threshold isocorrelational model fit best, in which different syndromes are conceptualized as different severities of one underlying dimension rather than as having separate aetiologies. Thus, MA and MoA were found to be different forms of the same disorder, with MA occupying the more extreme end of the spectrum of liability. Implications for our understanding of the relationship between migraine and depression are discussed.

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Depression, migraine with aura and migraine without aura: their
familiality and interrelatedness
HA Ball1, Z Samaan1, S Brewster2, N Craddock3,4, M Gill5, A Korszun6, W Maier7, L Middleton8, O Mors9,
MJ Owen3, J Perry2, M Preisig10, J Rice11, M Rietschel12, L Jones4, I Jones3, AE Farmer1& P McGuffin1
1Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London,6Barts and
The London, Queen Mary’s School of Medicine and Dentistry and8Division of Neurosciences and Mental Health, Imperial College, London,
2GlaxoSmithKline, Research and Development, Greenford,3Department of Psychological Medicine, School of Medicine, Cardiff University,
Cardiff and4Department of Psychiatry, University of Birmingham, Birmingham, UK,5Department of Psychiatry, Trinity Centre for Health
Sciences, Dublin, Ireland,7Department of Psychiatry, University of Bonn, Bonn and12Central Institute of Mental Health, Mannheim,
Germany,9Centre for Psychiatric Research, University of Aarhus, Aarhus, Denmark,10Department of Adult Psychiatry, University Hospital
of Lausanne, Prilly-Lausanne, Switzerland, and11Department of Psychiatry, Washington University, St Louis, MO, USA
Ball HA, Samaan Z, Brewster S, Craddock N, Gill M, Korszun A, Maier W,
Middleton L, Mors O, Owen MJ, Perry J, Preisig M, Rice J, Rietschel M, Jones L,
Jones I, Farmer AE & McGuffin P. Depression, migraine with aura and migraine
without aura: their familiality and interrelatedness. Cephalalgia 2009. London.
ISSN 0333-1024
Migraine is frequently comorbid with depression. There appear to be common
aetiological factors for both disorders, but the aetiology of migraine within
depressed patients, in particular the significance of aura, has been little studied.
A large sample of concordantly depressed sibling pairs [the Depression-Network
(DeNT) sample] was assessed as having migraine with aura (MA), migraine
without aura (MoA), probable migraine or no migraine according to Interna-
tional Headache Society guidelines. Correlations between siblings’ migraine
status were used to assess the nature of familial liability to migraine. A multiple
threshold isocorrelational model fit best, in which different syndromes are
conceptualized as different severities of one underlying dimension rather than as
having separate aetiologies. Thus, MA and MoA were found to be different
forms of the same disorder, with MA occupying the more extreme end of the
spectrum of liability. Implications for our understanding of the relationship
between migraine and depression are discussed. ?Migraine disorders, depression,
genetics, comorbidity
Harriet A. Ball, MSc, MRC SGDP Centre, Institute of Psychiatry, King’s College
London, London SE5 8AF, UK. Tel. + 44-207-848-5415, fax + 44-207-848-0866,
e-mail harriet.ball@iop.kcl.ac.uk Received 6 August 2008, accepted 12 October 2008
Contributions of authors
H.A.B. and Z.S. contributed equally to this work.
H.A.B. performed the model fitting analysis and wrote the first draft. Z.S. conceived the migraine component of the DeNt
study, designed the migraine questionnaire and tested its reliability. A.E.F. and P.McG. were overall study Principal
Investigators (PIs), designed the DeNt study and contributed to revising the draft; A.E.F. trained and supervised the
interviewers. P.McG. wrote the TETCOR program and supervised the statistical analyses. S.B., L.M. and J.P. obtained the
funding from Glaxo Wellcome, recruited site PIs and oversaw the quality of data collection, handling and analysis. The
following authors were the individual site PIs in charge of all aspects of subject recruitment and data quality locally: OM
Aarhus site, N.C., L.J. and I.J. (joint) Birmingham site, M.R. and W.M. (joint) Bonn site, A.K. and M.J.O. (joint) Cardiff site, M.G.
Dublin site, M.P. Lausanne site, A.E.F. and P.McG. (joint) London site and J.R. St Louis site. All authors have read and approved
the contents of the final manuscript.
doi:10.1111/j.1468-2982.2008.01808.x
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Introduction
The International Headache Society (IHS) opera-
tional criteria for migraine were first published in
1988 (1) and subsequently revised in 2004 (2). The
criteria identify two main categories of migraine:
migraine with aura (MA) and migraine without
aura (MoA). The diagnostic criteria for MA are
essentially those for MoA plus particular aura
symptoms, therefore the aetiological mechanisms
leading to MoA may also contribute to MA.
However, the aura phenomenon may be the result
of a different set of pathophysiological mechanisms.
Family studies have shown generally higher than
population incidence of migraine in relatives of
migraineurs of the same type (i.e. higher incidence
of MoA in the first-degree relatives of probands
with MoA) (3, 4). Similarly, twin concordance of the
same subtype of migraine is higher in monozygotic
than in dizygotic twins (5, 6), suggesting that the
familial similarity is due to genetic rather than
family environmental reasons. Some studies have
examined the cross-prevalence of MA and MoA
(e.g. MA in probands and MoA in relatives)—such
cross-prevalences could suggest an overlap in the
aetiology of the two disorders. Two twin studies
have supported this overlap in aetiology (7, 8), but
earlier twin and family studies did not (4, 9). An
overlap in aetiology is also suggested by the fre-
quent co-occurrence of MA and MoA within the
same individual (10) and within the same family
(11).
It has been suggested that the two syndromes are
variants of one underlying liability continuum, with
MA representing the more severe end of the con-
tinuum, rather than two distinct aetiologies. Two
previous twin studies (7, 8) found that a multiple
threshold model fit the data well (with MA being
represented by a more extreme threshold than that
for MoA) (Fig. 1). This implies that MA is a more
extreme form of the migraine phenotype, although
it does not necessarily imply that impairment is
more extremein MA
However, these studies focused on cases as defined
using latent class analysis, rather than the stricter
and well-defined criteria of the IHS.
The current study aimed to replicate and further
characterize this finding of a single underlying phe-
notype, using the stricter IHS criteria for migraine,
and examining migraine in the context of depres-
sion. A sample of siblings was used, who were
concordant for lifetime depression. The high comor-
bidity between migraine and depression (12) also
makes this a sample of convenience, as the high
comparedwithMoA.
prevalence of migraine gives more power to detect
relationships than in a general population sample
of the same size. Just under a half of migraineurs
have had major depressive disorder (13–15), and
the lifetime-ever risk of comorbidity is likely to be
even higher given that the first onset of major
depressive disorder may occur in mid to late adult-
hood (16). Thus, a history of or susceptibility to
depression could well be the norm rather than
the exception in migraineurs, and so examining
migraine within the context of depression could be
useful to determine if the same processes occur
relative to migraineurs as a whole.
The comorbidity between migraine and depres-
sion suggests that there could be some aetiological
risk factors shared between the two disorders, and
this is further supported by a finding of a ‘bidirec-
tional’ relationship (rather than one of the disorders
usually preceding the other) (14). The overall
hypothesis we aimed to test was that MA is the
extreme end of the continuum of liability to
migraine, rather than having a qualitatively differ-
ent aetiology to MoA.
The current study tested the isocorrelational
model (this is the basic form of the multiple thresh-
old model, which posits that the familial correla-
tions within both types of migraine are the same
magnitude as the cross-correlations) (17). The
current study also tested the ‘environmental’ or
isoproportional model, which posits that the same
genetic factors underlie the two phenotypes, but
the level of non-familial environmental influence
Frequency
Participants without
migraine
Participants
with migraine
with aura
Participants
with migraine
without aura
Liability to migraine
Figure 1 Two-threshold model for liability to migraine.
Individuals with migraine without aura are those with a
moderately high liability; individuals with migraine with
aura have the highest liabilities.
2
HA Ball et al.
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or measurement inaccuracy differs in the two
phenotypes.
Methods
Subjects
The study population comprised subjects from the
Depression-Network (DeNT) study, an affected
sibling pair genetic linkage study that has been
described in detail elsewhere (18). Briefly, the
sample consisted of sib pairs concordant for
lifetime-ever International Classification of Dis-
eases, 10th edn (19) and/or Diagnostic and Statis-
tical Manual, 4th edn (20) operational criteria for
recurrent unipolar depression (two or more epi-
sodes of at least moderate severity). Subjects were
identified from eight different sites in Europe and
North America and were interviewed using the
Schedules for Clinical Assessment in Neuropsy-
chiatry (21) to establish the diagnosis of depres-
sion. Pairs were excluded if either sibling had
symptoms meeting criteria for mania, hypomania
or schizophrenia, or if they had psychotic symp-
toms that were mood incongruent or present in
the absence of mood disturbance. Other exclusion
criteria were drug dependency, depression only in
the context of alcohol use or secondary to medical
illness or medication, or if any first-degree rela-
tives of either sib had ever been diagnosed with
bipolar disorder,schizophrenia,
disorder or acute or transient psychotic disorders.
All sites obtained ethical approval for the DeNt
study within their own countries and institutions.
Allstudyparticipants
consent for participation.
As part of an investigation of the study partici-
pants’ physical health, subjects were also inter-
viewed using a migraine questionnaire designed to
evaluate the lifetime ever occurrence of migraine
and other types of headache, according to the cri-
teria of the IHS (2004) (2). The majority were inter-
viewed in person, but a few were interviewed by
telephone. Subjects were assigned to one of the
following IHS categories; MA, MoA, probable
migraine (PM), non-migraine or tension headache
(OH) and no headache (NH). The validating char-
acteristics of the migraine interview were deter-
mined bycomparing the
obtained from the interview with that of a Consult-
ant Neurologist in 41 clinical subjects attending the
City of London Migraine Clinic. Compared with a
Consultant Neurologist diagnosis, the migraine
interviewhadexcellent
schizo-affective
gave writteninformed
headachediagnosis
specificity(1.00)and
modest sensitivity (0.66). In addition, for 20 of the
depressed subjects, the test–retest reliability of the
lifetime ever diagnosis of migraine was determined
over a mean interval of 3 years (range 1–4 years).
Spearman’s correlation coefficient (r) was 0.84
(P < 0.001).
For the purposes of the present analyses, MA
alone was considered as the narrow form of the
phenotype, MA plus MoA plus PM were considered
as the broad form of the phenotype, while OH plus
NH were considered to indicate the absence of the
phenotype. This ordinal classification balanced the
need for sufficient participants in each category
while assessing the status of aura as a marker of the
aetiologically most extreme end of the migraine
dimension.
The location of participants was as follows:
Aarhus, Denmark, n = 54; Birmingham, UK, n = 148;
Bonn, Germany, n = 154; Cardiff, UK, n = 137;
Dublin, Ireland, n = 164; Lausanne, Switzerland,
n = 34; London, UK, n = 91; St Louis, MO, USA,
n = 270. The English version of questionnaires was
used, but for the 23% of participants in non-English
speaking countries, it was translated into the local
language.
Although a sibship with n affected members
yields n(n-1)/2 sib pairs, these are not statistically
independent (22), and so utilizing all pairs overes-
timates the relative information contributed by
large sibships. Therefore, we examined only n - 1
pairs from each sibship (23) (effectively, taking this
subset to be representative of all pairs in a family
but giving a lower weighting to pairs in larger
sibships),whichisa
approach for use in genetic analyses of affected sib
pairs (24).
sufficiently conservative
Statistical analyses
The relationship between the narrow and broad
forms of migraine was explored using a two-
threshold model (17). A general model is fitted
which estimates four correlations: between the
narrow form in both sibs (r11), between the broad
form in both sibs (r22) and between the narrow
form in the first sib with the broad form in the
second sib and vice versa (r12 and r21). An isocor-
relational model (where all four correlations are set
to be equal) should fit if both forms of the disorder
are on the same continuum of liability, and if the
narrow form simply represents the more extreme
end of the continuum compared with the broad
form. The isoproportional model (where r12 and
r21 are set to be equal to one another, and equal to
Depression and migraine: familial liability
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the square root of the product of r11 and r22)
should fit if the two forms represent the same
continuum of liability but that one form is influ-
enced more heavily by non-familial environment or
measurement error. The independent model (in
which r12 and r21 are set to zero) should fit if the
narrow and broad forms are actually separate dis-
orders in which there is no family-aetiological
overlap.
The isocorrelational model, the isoproportional
model and the independent model can be com-
pared with the general model, by examining the
increase in the c2fit of the model relative to the
degrees of freedom of the comparison. In addition,
the isocorrelational model can be compared with
the isopoportional model by means of a c2com-
parison since the former is nested within, i.e. is a
special case of, the latter: the isocorrelational model
is a form of the isoproportional model in which the
non-familial environment and measurement error
‘are equally prominent in both forms’ (17).
Model fitting was performed using TETCOR, a
FORTRAN program written in-house that imple-
ments the models of Reich et al. (17). Polychoric
correlations between siblings on the two-threshold
migraine disorder were performed in the Stata sta-
tistical program (StataCorp LP, College Station, TX,
USA) (25).
Results
Recurrently
female (75%) and 267 male (25%)] from 495 White
families participated in the migraine study. Because
some families had more than two affected siblings
(443 families had two affected siblings, 44 families
had three, six families had four and two families
had five), and because we utilised n - 1 pairs from
each sibship consisting of n affected members, there
were 557 sibling pairs in total, comprising 321
female–female pairs, 44 male–male pairs and 192
mixed sex pairs.
depressedsubjects [n = 1052;785
The mean age of the participants was 45.6 years
(S.D. 11.7, range 18.8–80.4 years); the probands’
mean age was 46 years (S.D. 11.5, range 20.2–80.4
years) and siblings’ mean age was 45.2 years (S.D.
11.9, range 18.8–78.4 years).
The frequency of headache in the depressed
sibling pairs is shown in Table 1: 37% of the
probands and the siblings had had migraine
(MA + MoA + PM).Female
higher prevalence of migraine (42%) compared with
male subjects (22%) (z = 5.85, P < 0.001). The sibling
concordance rates are shown in Table 2. When the
probands had the narrow form of the disorder there
were more siblings affected by the narrow form
(MA) and more siblings affected overall (i.e. broad
form: MA + MoA + PM).
parametric test for trend across ordered groups was
conducted in Stata, with the siblings in mutually
exclusive categories (MA/MoA + PM/NH + OH),
the result was highly significant (z = 3.62, P < 0.001)
in the hypothesized direction. This pattern is con-
sistent with the broad and narrow forms being on
the same continuum of genetic liability, but with the
narrow form being at the more extreme end of the
distribution. This was then formally tested using
model fitting (below).
subjects showeda
Thus,whenanon-
Model fitting
The results of model fitting are shown in Table 3.
Theindependent model
(P < 0.01), indicating that there are common aetio-
logical influences on both forms of the disorder
(MoA and MA). The isoproportional and the
isocorrelational models both fit the data well
(c2difference = 2.76, d.f. = 2, P = 0.25; c2differ-
ence = 3.49, d.f. = 3, P = 0.33, respectively), indicat-
ing that the two forms of migraine fit a model in
which the narrow form is simply the result of the
more extreme end of the genetic liability distribu-
tion compared with the broad form. The isocorre-
lational model is preferred because it is more
revealedapoor fit
Table 1 Number of probands and siblings with different types of headache according to the International Headache
Society criteria for migraine
Headache typeProbandsSiblingsTotal
No recurrent headache (NH)
Non-migraine headache (OH)
Probable migraine (PM)
Migraine without aura (MoA)
Migraine with aura (MA)
Total
150 (30.3%)
164 (33.1%)
75 (15.2%)
44 (8.9%)
62 (12.5%)
495 (100%)
179 (32.1%)
172 (30.9%)
106 (19%)
44 (7.9%)
56 (10%)
557 (100%)
329 (31.3%)
336 (32%)
181 (17.2%)
88 (8.3%)
118 (11.2%)
1052 (100%)
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parsimonious and not a significantly worse fit than
the isoproportional model (c2
d.f. = 1, P = 0.39).
The polychoric sib correlation for migraine, when
assuming a two-threshold model as supported by
the above models, was 0.22 [95% confidence inter-
val (CI) 0.12, 0.32]. We cannot calculate variance
components as the sample comprises full sibs only.
However, if we assume this familial resemblance is
best explained by only additive genetic rather than
shared family environmental effects, as has been
found in previous twin studies (5, 6, 19), then this
would correspond to an additive genetic effect
(heritability) of 44%.
In order to examine the effect of sex, the analyses
were repeated in the female–female sib pairs
(N = 321). The results of the model fitting were the
same. The polychoric sib correlation for female–
female pairs assuming a two-threshold model was
0.30 (95% CI 0.16, 0.44); thus, it was higher than the
correlation estimated using all sex sib pairs, but not
significantly so.
difference = 0.72,
Discussion
Consistent with previous studies that used general
population samples and different criteria to identify
cases (7, 8), the present study supports the hypoth-
esis that MA represents the extreme end of a con-
tinuum of migraine familial liability, even when
examined in depressed participants. Therefore,
these results contradict studies (4, 9) that present
MA and MoA as two separate disorders with sepa-
rate aetiologies. However, latent class analysis has
shown that presence or absence of aura did not
strongly correspond to the severity of the migraine
or neurological symptoms (7, 8). The conceptualiza-
tion of MA as the most extreme form of the disorder
in terms of aetiology is still consistent with evi-
dence that the actual migraines are reported as
being more severe in MoA (26).
The present study has demonstrated that the
continuum of liability to migraine is also a valid
hypothesis when strict IHS criteria are used, and
withina depressed population. Althoughthe
Table 2 Sibling concordance for migraine in the DeNT sample
Sibling
NH + OH:
No migraine (%)Total N
MA + MoA + PM (broad form)
Proband*
MA + MoA + PM
(broad form)
NH + OH: No migraine
Total N
MA: narrow form (%)
13 (18)
11 (8)
32 (9)
56
MoA + PM (%)
25 (35)
45 (33)
80 (23)
150
MA: Narrow form
MoA + PM
33 (46)
79 (59)
239 (68)
351
71
135
351
557
*The 557 probands are 495 individuals, 62 of whom are counted more than once in order to include analyses between the
proband and extra siblings.
MA, migraine with aura; MoA, migraine without aura; PM, probable migraine; NH, no headache; OH, non-migraine or
tension headache.
Table 3 Results of two-threshold model fitting to determine the nature of the relationship between the broad and narrow
forms of migraine
Model*
c2of model compared
with general model d.f.
P
c2of model compared
with model 2d.f.
P
1. Independent
2. Isoproportional
3. Isocorrelational
15.71
2.76
3.49
2
2
3
0.0004
0.2516
0.3221
–
–
0.73
–
–
1
–
–
0.3929
*The general model estimates the correlations between broad and narrow forms of the disorder in probands and siblings;
the independent model fixes the cross-correlations (between broad and narrow forms) to zero; the isoproportional and
isocorrelational models allow cross-correlations such that the narrow form has a higher familial loading than the broad form,
but in addition the isoproportional model allows for different non-familial or measurement error contributions to the two
forms of the disorder.
Bold indicates best fitting model.
Depression and migraine: familial liability
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selection of our sample limits the extent to which
our findings can be extrapolated to migraineurs as
a whole, the phenotypes of migraine are similar in
depressed people to those in the general popula-
tion, excepting the higher prevalence seen in the
context of depression (12). This may be consistent
with the hypothesis that the comorbidity between
migraine and depression is due to shared aetiologi-
cal risk factors, with depressed people having more
of those risk factors than the general population.
That is, on top of the familial factors that predis-
pose to depression, which we have over-ascertained
in this sample of concordantly depressed sib pairs,
there are familial influences on the continuum of
liability to migraine.
It is also possible that, in the general population,
the same factors that confer familial liability to
depression also confer familial liability to migraine.
If there are such common liability factors, we would
expect to find a stronger association with depres-
sion in aetiologically more severe cases of migraine.
Indeed, a recent case–control comparison found a
stronger association of lifetime-ever major depres-
sion with MA than with MoA (27). If these familial
liability factors are genetic (as suggested by the lack
offamilial-environmental
depression (28) or migraine (29)), then by concen-
trating on aetiologically more severe migraineurs
(who can be approximately indexed by the presence
of aura), we may achieve the greatest power to
detect genes in molecular studies. Furthermore,
where genes are identified as contributing to
migraine, some may also influence liability to
depression.
influences oneither
Limitations
The participants in this study may not be fully
representative of the whole depressed population,
because they have a similarly affected sibling.
However, past research has not supported the
hypothesis that there is a ‘genetic’ subtype of
depression that is aetiologically different from a
‘non-genetic’ subtype (30). Comorbidity between
anxiety and depression could mean that anxiety is
acting as a confounding factor in the prevalence
rate of migraine in this sample. However, past
research has suggested that although anxiety levels
are higher in migraineurs than in non-migraineurs,
there appears to be no relationship between anxiety
and the presence or absence of aura (31), so the
particular relationships tested in this study are
unlikely to be affected. The exclusion criteria (e.g.
mania, psychosis, drug dependency) mean that our
sample does not reflect all possible presentations of
depression, and so these exclusions may have led
to some confounding of the prevalence rate of
migraine; however, these exclusions give us a rela-
tively homogeneous sample in which to test our
hypotheses concerning the aetiology of migraine in
the context of unipolar depression. Furthermore,
this study can only indirectly (in combination with
previous reports of comorbidity in population-
based samples) tell us about the relationship
between migraine and depression because the
current sample contains only those who have had
depression.
Another limitation of the study was the use of a
questionnaire-based interview rather than clinical
opinion; nonetheless, the interview was found to
have reasonable test–retest reliability, and specificity
and sensitivity when judged against the diagnoses of
an expert neurologist. The questionnaire-based
method on average resulted in a narrower definition
of migraine. However, this would tend to reduce
power to distinguish between models rather than
create false-positive findings.
In conclusion, this study suggests that MA is
typically the result of a greater dose of the same
causal risk factors that lead to MoA. Some of
these risk factors are shared within families and
are likely to be genetic. This was found even
within the current depressed sample, which shows
that (i) similar aetiological processes are involved
in the general population of migraineurs as in
those who also have experiences of depression,
and (ii) the relationship between MA and MoA is
not explained by confounding by depression. The
higher prevalence of migraine within depressed
samples, and the more extreme aetiological posi-
tion of migraine with than without aura, suggests
that future research looking for specific causal risk
factors (genetic or otherwise) for any of these
three disorders may achieve the greatest power
by focusing on patients comorbid for depression
and MA.
Competing interests
M.J.O. and N.C. have acted as consultants to GlaxoSmith-
Kline (GSK) and have received honoraria for academic talks
from Eli Lilly, Astra Zeneca and GSK. A.K. has received
research grants from GSK and Synthelabo-Sanofi and has
received honoraria from Eli Lilly. A.E.F. has received hono-
raria for presentations and chairing meetings from Eli Lilly,
GSK and Wyeth and is a consultant for GSK. P.McG. has
received honoraria from Eli Lilly and GSK and has acted as
a consultant in the recent past for GSK and Astra Zeneca.
6
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Acknowledgement
This study was funded by GlaxoSmithKline.
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