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The aetiology of anorexia nervosa is multifactorial and consists ofa complex combination of genetic and environmental factors.Population-based twin studies estimate a heritability between28 and 74%.14 Anorexia nervosa is often associated withcomorbid psychiatric disorders, such as depression, anxiety,obsessivecompulsive, personality and substance use disorders.1,5,6
Familial and population-based studies report co-occurrence ofanorexia nervosa and autism spectrum disorders (ASD) infamilies7 and an overrepresentation of ASD in individuals witheating disorders.8 Finally, in recent years a number of clinicaland neuropsychological studies support the existence of sharedtraits between individuals with anorexia nervosa and ASD,including problems with central coherence, set-shifting and theoryof mind in both disorders.914 These traits could present sharedendophenotypes of anorexia nervosa and ASD, which characteriseindividuals or specific subgroups of individuals with anorexianervosa; subgroups that may represent those who have aprolonged or chronic course of illness.5,14,15 Moreover, someauthors have hypothesised that spectrum traits may manifest asanorexia nervosa in females and as ASD in males.10 Tailoringtreatment for those subgroups of individuals with anorexianervosa who either have comorbid ASD or subthreshold autismspectrum symptoms and traits might alter the course of anorexianervosa in a favourable direction.16 It is therefore important toidentify and to describe the co-occurrence of ASD in individualswith anorexia nervosa and in their families and vice versa.
Clinical and population-based studies describing the coexistenceof anorexia nervosa and ASD in families or on the psychologicaltraits of social cognition are, however, limited by small samplesof predominantly females (Rastam 2003, n=51; Wentz 2005,
n= 30).6,8,17 Confirmatory evidence in large population-basedsamples does not yet exist. In Denmark we have access to data frompublic national registers with information on all people admitted tohospital for psychiatric disorders since 1969 onwards.18 The aim ofthis study was to investigate the co-occurrence of anorexia nervosaand ASD in probands and in their first- and second-degree relativesin a nationwide study. We hypothesised (a) that ASD would beoverrepresented in probands with anorexia nervosa and vice versa(comorbidity) and (b) in their families (cross-diagnostic geneticliability) and (c) that we could identify a doseresponse effect ofthe presence of ASD in these relatives according to the degree ofshared genetic material as a measure for a common geneticaetiology for anorexia nervosa and ASD. Finally, we repeated allanalyses for comorbid and familial major depression and anypsychiatric disorder, to determine whether any observed associationswere specific to anorexia nervosa and to ASD.
Method
Study population
We identified all individuals born in Denmark from 1 May 1981 to31 December 2008 in the Danish Civil Registration System.19 Theregister includes the personal identification number, gender, dateof birth, continuously updated information on vital status andparents identification numbers. The identification number is usedas a personal identifier in all national registers, enabling uniquelinkage between registers. We excluded those lacking a link tothe mother and to information on parental ages at date of thechilds birth (n= 11 536 (0.7%) individuals, mostly lackinginformation on paternal age).
401
Autism spectrum disorder in individualswith anorexia nervosa and in their first- andsecond-degree relatives: Danish nationwideregister-based cohort-studySusanne V. Koch, Janne T. Larsen, Svend E. Mouridsen, Mette Bentz, Liselotte Petersen,Cynthia Bulik, Preben B. Mortensen and Kerstin J. Plessen
BackgroundClinical and population-based studies report increasedprevalence of autism spectrum disorders (ASD) in individualswith anorexia nervosa and in their relatives. No nationwidestudy has yet been published on co-occurrence of thesedisorders.
AimsTo investigate comorbidity of ASD in individuals with anorexianervosa, and aggregation of ASD and anorexia nervosa intheir relatives.
MethodIn Danish registers we identified all individuals born in19812008, their parents, and full and half siblings, and linkedthem to data on hospital admissions for psychiatric disorders.
ResultsRisk of comorbidity of ASD in probands with anorexia
nervosa and aggregation of ASD in families of anorexianervosa probands were increased. However, the risk ofcomorbid and familial ASD did not differ significantly fromcomorbid and familial major depression or any psychiatricdisorder in anorexia nervosa probands.
ConclusionsWe confirm aggregation of ASD in probands with anorexianervosa and in their relatives; however, the relationshipbetween anorexia nervosa and ASD appears to be non-specific.
Declaration of interestC.B. is a consultant for Shire Pharmaceuticals.
Copyright and usageB The Royal College of Psychiatrists 2015.
The British Journal of Psychiatry (2015)206, 401407. doi: 10.1192/bjp.bp.114.153221
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Assessment of anorexia nervosa,ASD and any mental disorder
Individuals in the study population, their parents, and their fulland half siblings were linked with the Danish Psychiatric CentralResearch Register,18 which registers all admissions to Danishpsychiatric in-patient facilities since 1 April 1969, and with theDanish National Patient Register,20 which registers alladmissions to somatic in-patient facilities since 1 January 1977.Since 1995 and onwards, the National Patient Register has alsoincluded psychiatric contacts in general hospitals, and both theNational Patient Register and the Psychiatric Central ResearchRegister have included information on out-patient contacts aswell. Until 31 December 1993, the diagnostic system usedwas ICD-8,21 and since 1 January 1994, the diagnostic systemICD-1022 has been used.
Given our aim to study comorbidity between anorexia nervosaand ASD in an individual, we included all members of thepopulation classified as having anorexia nervosa or atypical anorexia(that is ICD-8 code 306.5x or ICD-10 code F50.0-F50.1) or infantileautism, atypical autism or Asperger syndrome (ICD-8 code299.00-299.01 or ICD-10 code F84.0-F84.1, F84.5) if they had arecord in the National Patient Register or Psychiatric CentralResearch Register of in- or out-patient care for that disorder. Casesof anorexia nervosa were not counted before the age of 9 years,because those diagnoses represented childhood eating disordersand not fully developed anorexia nervosa.23
In a second step, to study familial aggregation of the twodisorders, we included index probands and their parents and siblingsdiagnosed with eating disorder (ICD-8 code 306.5 or ICD-10 codeF50.0-F50.1, F50.8), ASD (ICD-8 code 299.00-299.01 or ICD-10code F84.0-F84.1, F84.5, F84.8-F84.9), major depression (ICD-8code 296.09, 298.09 or ICD-10 code F32, F33) or any psychiatricdisorder (ICD-8 code 290-315 or ICD-10 code F00-F99), if theyhad a record of in- or out-patient care for that disorder. The dateof onset was defined as the first day of the first contact (in- orout-patient) leading to a diagnosis of that particular disorder.
Study design
A total of 1 724 189 people born in Denmark were followed upfrom date of birth until the first diagnosis with the disorder ofinterest, death, emigration from Denmark or 31 December 2012,whichever came first. The Danish Data Protection Agency hasapproved the study.
Statistical analysis
We estimated hazard ratios (HR; using Cox regression in Stata 12for Windows) for both anorexia nervosa and ASD for probands,who had anorexia nervosa or ASD, respectively, or were exposedto a first- or second degree relative with one or the other ofthe disorders, to detect co-occurrence of anorexia nervosa andASD independent of the sequence of the disorders.24 Moreover,we compared HRs for anorexia nervosa and ASD, respectively,in probands of families with major depression or any psychiatricdisorder to distinguish between a specific effect of co-occurrenceof the two disorders or a general psychiatric vulnerability. Analyseswere adjusted for maternal and paternal age, for calendar time(to adjust for birth-cohort effect) as a time-dependent variableand for gender by means of separate underlying hazardfunctions. Calendar time was categorised as 19811984, 19851989, 19901992, 19931994, 19951999, 20002004, 20052010and 20112012 taking into account the above mentioned changesin registration practice over time. Maternal age was categorised asless than 20 and 20 or older, whereas paternal age was categorisedas less than 20, 2039 and 40 or older according to how parental
age acts as a risk factor for psychiatric illness in the offspring.25
Familial psychiatric history was coded as time-dependent variablesfor probands, first-degree relatives (mothers, fathers and fullsiblings) and second-degree relatives (maternal and paternal halfsiblings) separately. Individuals without second-degree relativesand those without registry-identified fathers were analysedseparately. Furthermore, we performed supplementary analyses ofgender and age at outcome-diagnosis stratified by age 516 and516 years of age (results not shown). We used 2-tailed chi-squaretest for descriptive statistics.
Results
In the study population of 1 724 189 individuals, we identified5006 individuals (358 males, 4648 females; male:female ratio1:13.0) who had a diagnosis of anorexia nervosa, and 12 606individuals (10 012 males, 2594 females; male:female ratio 3.9:1)with a diagnosis of ASD (Table 1). In total, 45.8% of the femalesand 58.4% of the males were diagnosed with anorexia nervosa forthe first time before the age of 16 years (P50.001). More femaleswere given a first diagnosis of infantile or atypical autism (64.4%v. 59.1%, P=0.009) and fewer a diagnosis of Asperger syndrome(35.6% v. 40.9%, P50.001) before the age of 16 years comparedwith the males.
Probands
Risk of ASD in probands with anorexia nervosa
Probands with a first diagnosis of anorexia nervosa, had a highlyelevated risk of receiving a second diagnosis of ASD (HR=15.08,95% CI 12.2318.58) (Table 2). This risk for males (HR= 22.04,95% CI 15.3931.58) was higher than for females (HR= 12.82,95% CI 9.9416.53). Males with anorexia nervosa had a higherrisk of a late autism spectrum diagnosis (516 years of age),whereas females with anorexia nervosa were equally diagnosedwith ASD before and after the age of 16 years (results not shown).However, we found an even higher risk for being diagnosed withASD in probands, whose first diagnosis was major depression(HR= 34.76, 95% CI 31.5138.36).
Risk of anorexia nervosa in probands with ASD
Likewise, probands, who had ASD as their first diagnosis, had anelevated risk of having a second diagnosis of anorexia nervosa(HR= 5.39, 95% CI 4.376.64) (Table 2) with no differences withrespect to gender or age at anorexia nervosa diagnosis (results notshown). The risk of developing anorexia nervosa, however, waseven higher after an initial diagnosis of major depression(HR= 17.67, 95% CI 16.1219.36).
Family history
Risk of ASD with a family history of anorexia nervosa
A family history of anorexia nervosa was associated with anelevated risk of receiving a diagnosis of ASD (Table 3). The HRfor being diagnosed with ASD if a first-degree relative hadanorexia nervosa was 1.80 (95% CI 1.432.28) and the HR was1.44 (95% CI 0.942.21), if a second-degree relative had anorexianervosa. However, these HRs were of the same magnitude asthose seen in families with a history of major depression (HRfor first-degree relatives 1.78 (95% CI 1.651.92) and HR forsecond-degree relatives 1.37 (95% CI 1.111.69)) and those infamilies with any psychiatric disorder (Table 3). We thus didnot find a doseresponse effect according to the degree of sharedgenetic material among relatives.
402
Koch et al
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Autism spectrum disorder and anorexia nervosa
Risk of anorexia nervosa with a family history of ASD
A family history of ASD also increased the risk of being diagnosedwith anorexia nervosa (HR= 1.45 (95% CI 1.091.94) for having afirst-degree relative with ASD and HR= 1.40 (95% CI 0.892.20)for having a second-degree relative with ASD) (Table 4). Similar tothe outcome of ASD, we did not observe a doseresponse effectaccording to the degree of shared genetic material among relatives.Furthermore, a family history of ASD yielded a significantly lowerrisk for developing anorexia nervosa compared with families witha history of anorexia nervosa (Table 4). Moreover, we observed anequally elevated risk for developing anorexia nervosa amongprobands, who had a family member with major depression(HR for first-degree relatives 1.34 (95% CI 1.191.51) and HRfor second-degree relatives 1.02 (95% CI 0.731.43)). Familieswith a history of any psychiatric disorder showed a similarpattern.
Familial aggregation of anorexia nervosa
A family history of anorexia nervosa was a risk factor fordeveloping anorexia nervosa with an HR of 3.92 (95% CI 3.124.93) if a first-degree relative had the disorder and an HR of 1.83(95% CI, 1.013.32) if a second-degree relative had the disorder(Table 4). This represents a dose response effect according tothe degree of shared genetic material and underscores the roleof genetic factors in the pathogenesis of anorexia nervosa. Asubanalysis showed that especially anorexia nervosa in mothersand sisters contributed to the increased risk (both genders);however, we identified only a few cases of anorexia nervosa amongfathers and brothers, which may have influenced the statisticalpower of the estimates (results not shown). Thus, we neither coulddetect any differential influences of a family history of anorexianervosa on the proband according to gender; nor did probandswith early diagnosis of anorexia nervosa seem to have a morepronounced aggregation of anorexia nervosa in the family.
Familial aggregation of ASD
Moreover, the risk for ASD was highly elevated when exposed toASD in a first- (HR= 7.79, 95% CI 7.158.50) and a second-degree relative (HR= 2.97, 95% CI 2.473.57) (Table 3). Femaleswere at highest risk (females HR= 10.24 (95 % CI 8.7112.04)v. males HR= 7.09 (95% CI 6.407.85)). ASD was most frequentlypresent in fathers and brothers (results not shown), but ASDamong the female members of the family also contributed tothe results.
Unspecific diagnoses
In additional analyses, we included a broader phenotype (theunspecific diagnoses of the two categories in ICD-10, such as codeF50.8 (eating disorders NOS) and code F84.8+.9 (ASD NOS),respectively) to explore the specificity of the findings, which didnot alter the main results.
Other effects
Additional analyses could not confirm any specific effect of any ofthe measured psychiatric disorders in half-siblings (divided intomaternal or paternal half-siblings), nor gender effects of full- orhalf-siblings. To exclude the possibility that unknown fatherscould have influenced the analyses, we repeated the analysesrestricted to families where all fathers were known, which alsodid not change the main findings.
403
Table
1Individuals
born
inDenmark,1May1981to
31December2008,whore
ceivedeitherafirstdiagnosis
ofanore
xia
nervosaorautism
spectrum
disord
ers
(ASD)bygenderandageatdiagnosis
Ageatdiagnosis
Ageatdiagnosis
Ageatdiagnosis
Diagnosis
All
516years
516years
Allfemales
516years
516years
Allmales
516years
516years
Anorexianervosa
500
6(100
.0)
233
6(100
.0)
267
0(100
.0)
464
8(100
.0)
212
7(10
0.0)
252
1(100
.0)
358(100
.0)
209(100
.0)
149(100
.0)
ASD
1260
6(100
.0)
1085
1(100
.0)
175
5(100
.0)
259
4(100
.0)
210
3(100
.0)
491(100
.0)
1001
2(100
.0)
874
8(100
.0)
126
4(100
.0)
Infantile/atypical
autism
712
6(56.5)
652
4(60.1)
602(34.3)
150
7(58.1)
135
4(64.4)
153(31.2)
561
9(56.1)
517
0(59.1)
449(35.5)
Asp
ergersyndrome
548
0(43.5)
432
7(39.9)
115
3(65.7)
108
7(41.9)
749(35.6)
338(68.8)
439
3(43.9)
357
8(40.9)
815(64.5)
Table
2Hazard
ratios(H
Rs)forinfantile
andatypicalautism,Asperg
ersyndro
me,andanore
xia
nervosaandatypicalanore
xia
giventh
epro
bandhasanore
xia
nervosa,autism
spectrum
disord
ers
(ASD)ormajordepre
ssiona
Probands
history
Allprobands
Female
probands
Male
probands
ofpsych
iatric
disorder
HR(95%
CI)
Controlgroup,n
(%)Case
group,n(%
)HR(95%
CI)
Controlgroup,n
(%)Case
group,n(%
)HR(95%
CI)
Controlgroup,n
(%)Case
group,n(%
)
HRforASD
Nega
tivehistory
ofan
orexianervosa
1.00
(Ref)
170
609
6(99.7)
1251
2(99.3)
1.00
(Ref)
83172
8(99.4)
253
0(97.5)
1.00
(Ref)
87436
8(100
.0)
998
2(99.7)
Positiv
ehistory
ofan
orexianervosa
15.08(12.2318.58)
548
7(0.3)
94(0.8)
12.82(9.9416.53)
508
6(0.6)
64(2.5)
22.04(15.3931.58)
401(0.1)
30(0.3)
Nega
tivehistory
ofdepression
1.00
(Ref)
169
092
1(98.8)
1210
0(96.0)
1.00
(Ref)
82227
1(98.3)
239
0(92.1)
1.00
(Ref)
86865
0(99.3)
971
0(97.0)
Positiv
ehistory
ofdepression
34.76(31.5138.36)
2066
2(1.2)
506(4.0)
32.83(27.8738.67)
1454
3(1.7)
204(7.9)
35.64(31.5240.30)
611
9(0.7)
302(3.0)
HRforan
orexianervosa
Nega
tivehistory
ofASD
1.00
(Ref)
170
138
0(99.0)
491
5(98.2)
1.00
(Ref)
83103
7(99.6)
458
0(98.5)
1.00
(Ref)
87034
3(98.4)
335(93.6)
Positiv
ehistory
ofASD
5.39(4.376.64)
1780
3(1.0)
91(1.8)
5.22(4.116.64)
372
3(0.5)
68(1.5)
5.75(3.768.82)
1408
0(1.6)
23(6.4)
Nega
tivehistory
ofdepression
1.00
(Ref)
169
883
8(98.8)
441
5(88.2)
1.00
(Ref)
82093
9(98.3)
409
6(88.1)
1.00
(Ref)
87789
9(99.3)
319(89.1)
Positiv
ehistory
ofdepression
17.67(16.1219.36)
2034
5(1.2)
591(11.8)
16.84(15.3218.51)
1382
1(1.7)
552(11.9)
46.10(32.4365.54)
652
4(0.7)
39(10.9)
a.Of172
418
9individualsborn
inDenmark1May
1981
to31
Dece
mber20
08,5
006(464
8women,3
58men)rece
ivedadiagn
osisofan
orexianervosa,leav
ing171
918
3co
ntrols(834
844women,8
8442
3men)a
nd12
606(259
4women,10
012men)rece
ivedadiagn
osis
ofinfantileoratyp
ical
autism
orAsp
ergersyndrome,leaving171
158
3co
ntrols
(836
814women,87
476
9men).Bold
indicatesign
ifica
ntresu
lts.
-
Koch et al
404
Table
3Hazard
ratios(H
Rs)forinfantile
andatypicalautism
andAsperg
ersyndro
megiventh
ere
lativeshaveanore
xia
nervosa,autism
spectrum
disord
ers
(ASD),majordepre
ssionorany
psychiatric
disord
era
Family
history
ofpsych
iatric
Allprobands
Female
probands
Male
probands
disorder/typeofrelative
HR(95%
CI)
Controlgroup,n
(%)Case
group,n(%
)HR(95%
CI)
Controlgroup,n
(%)Case
group,n(%
)HR(95%
CI)
Controlgroup,n
(%)Case
group,n(%
)
History
ofan
orexianervosa
First-degree,nega
tive
1.00
(Ref)
170
149
7(99.4)
1253
5(99.4)
1.00
(Ref)
83187
2(99.4)
257
8(99.4)
1.00
(Ref)
86962
5(99.4)
995
7(99.5)
First-degree,positiv
e1.80(1.432.28)
1008
6(0.6)
71(0.6)
1.84(1.133.01)
494
2(0.6)
16(0.6)
1.79(1.372.34)
514
4(0.6)
55(0.6)
Seco
nd-degree,nega
tive
1.00
(Ref)
46521
5(27.2)
425
2(33.7)
1.00
(Ref)
22802
3(27.3)
837(32.3)
1.00
(Ref)
23719
2(27.1)
341
5(34.1)
Seco
nd-degree,positiv
e1.44
(0.94
2.21
)286
5(0.2)
21(0.2)
2.54(1.275.11)
138
9(0.2)
8(0.3)
1.14
(0.66
1.96
)147
6(0.2)
13(0.1)
History
ofASD
First-degree,nega
tive
1.00
(Ref)
169
385
6(99.0)
1206
2(95.7)
1.00
(Ref)
82794
5(98.9)
243
5(93.9)
1.00
(Ref)
86591
1(99.0)
962
7(96.2)
First-degree,positiv
e7.79(7.158.50)
1772
7(1.0)
544(4.3)
10.24(8.7112.04)
886
9(1.1)
159(6.1)
7.09(6.407.85)
885
8(1.0)
385(3.9)
Seco
nd-degree,nega
tive
1.00
(Ref)
45905
4(26.8)
415
6(33.0)
1.00
(Ref)
22490
1(26.9)
815(31.4)
1.00
(Ref)
23415
3(26.8)
334
1(33.4)
Seco
nd-degree,positiv
e2.97(2.473.57)
902
6(0.5)
117(0.9)
3.62(2.515.21)
451
1(0.5)
30(1.2)
2.81(2.273.47)
451
5(0.5)
87(0.9)
History
ofdepression
First-degree,nega
tive
1.00
(Ref)
159
854
1(93.4)
1185
2(94.0)
1.00
(Ref)
78109
2(93.3)
241
4(93.1)
1.00
(Ref)
81744
9(93.5)
943
8(94.3)
First-degree,positiv
e1.78(1.651.92)
11304
2(6.6)
754(6.0)
1.90(1.642.22)
5572
2(6.7)
180(6.9)
1.74(1.601.90)
5732
0(6.6)
574(5.7)
Seco
nd-degree,nega
tive
1.00
44920
9(26.3)
418
2(33.2)
1.00
22020
7(26.3)
820(31.6)
1.00
(Ref)
22900
2(26.2)
336
2(33.6)
Seco
nd-degree,positiv
e1.37(1.111.69)
1887
1(1.1)
91(0.7)
1.68(1.132.51)
920
5(1.1)
25(1.0)
1.28(1.011.64)
966
6(1.1)
66(0.7)
History
ofan
ypsych
iatricdisorder
First-degree,nega
tive
1.00
(Ref)
130
796
5(76.4)
931
1(73.9)
1.00
(Ref)
63823
0(76.3)
187
7(72.4)
1.00
(Ref)
66973
5(76.6)
743
4(74.3)
First-degree,positiv
e2.02(1.942.10)
40361
8(23.6)
329
5(26.1)
2.02(1.852.20)
19858
4(23.7)
717(27.6)
2.02(1.932.11)
20503
4(23.4)
257
8(25.8)
Seco
nd-degree,nega
tive
1.00
(Ref)
36181
7(21.1)
352
1(27.9)
1.00
(Ref)
17724
7(21.2)
671(25.9)
1.00
(Ref)
18457
0(21.1)
285
0(28.5)
Seco
nd-degree,positiv
e1.46(1.341.58)
10626
3(6.2)
752(6.0)
1.62(1.371.91)
5216
5(6.2)
174(6.7)
1.42(1.291.55)
5409
8(6.2)
578(5.8)
a.Of172
418
9people
born
inDenmark1May
1981
to31
Dece
mber20
08,12
606(259
4women,10
012men)rece
ivedadiagn
osisofinfantileoratyp
ical
autism
orAsp
ergersyndrome,leaving171
158
3co
ntrols
(836
814women,87
476
9men).Bold
indicate
sign
ifica
ntresu
lts.
Table
4Hazard
ratios(H
Rs)foranore
xia
nervosaandatypicalanore
xia
giventh
ere
lativeshaveanore
xia
nervosa,autism
spectrum
disord
ers
(ASD),majordepre
ssionoranypsychiatric
disord
era
Family
history
ofpsych
iatric
Allprobands
Female
probands
Male
probands
disorder/typeofrelative
HR(95%
CI)
Controlgroup,n(%
)Case
group,n(%
)HR(95%
CI)
Controlgroup,n(%
)Case
group,n(%
)HR(95%
CI)
Controlgroup,n(%
)Case
group,n(%
)
History
ofan
orexianervosa
First-degree,nega
tive
1.00
(Ref)
170
911
3(99.4)
493
1(98.5)
1.00
(Ref)
82991
6(99.4)
457
8(98.5)
1.00
(Ref)
87919
7(99.4)
353(98.6)
First-degree,positiv
e3.92(3.124.93)
1007
0(0.6)
75(1.5)
3.92(3.104.97)
484
4(0.6)
70(1.5)
3.84(1.599.30)
522
6(0.6)
5(1.4)
Seco
nd-degree,nega
tive
1.00
(Ref)
46800
3(27.2)
145
4(29.0)
1.00
(Ref)
22751
0(27.3)
135
2(29.1)
1.00
(Ref)
24049
3(27.2)
102(28.5)
Seco
nd-degree,positiv
e1.83(1.013.32)
288
5(0.2)
11(0.2)
1.79
(0.96
3.33
)138
5(0.2)
10(0.2)
2.44
(0.34
17.51)
150
0(0.2)
1(0.3)
History
ofASD
First-degree,nega
tive
1.00
(Ref)
170
050
8(98.9)
495
9(99.1)
1.00
(Ref)
82572
6(98.9)
460
3(99.0)
1.00
(Ref)
87478
2(98.9)
356(99.4)
First-degree,positiv
e1.45(1.091.94)
1867
5(1.1)
47(0.9)
1.51(1.132.03)
903
4(1.1)
45(1.0)
0.79
(0.20
3.16
)964
1(1.1)
2(0.6)
Seco
nd-degree,nega
tive
1.00
(Ref)
46166
3(26.9)
144
6(28.9)
1.00
(Ref)
22436
5(26.9)
134
5(29.0)
1.00
(Ref)
23729
8(26.8)
101(28.2)
Seco
nd-degree,positiv
e1.40
(0.89
2.20
)922
5(0.5)
19(0.4)
1.34
(0.83
2.17
)453
0(0.6)
17(0.4)
2.17
(0.53
8.82
)469
5(0.5)
2(0.6)
History
ofdepression
First-degree,nega
tive
1.00
(Ref)
160
530
2(93.4)
472
0(94.3)
1.00
(Ref)
77922
2(93.4)
439
2(94.5)
1.00
(Ref)
82608
0(93.4)
328(91.6)
First-degree,positiv
e1.34(1.191.51)
11388
1(6.6)
286(5.7)
1.28(1.131.46)
5553
8(6.7)
256(5.5)
2.11(1.453.07)
5834
3(6.6)
30(8.4)
Seco
nd-degree,nega
tive
1.00
(Ref)
45186
2(26.3)
143
1(28.6)
1.00
(Ref)
21970
4(26.3)
132
8(28.6)
1.00
(Ref)
23215
8(26.3)
103(28.8)
Seco
nd-degree,positiv
e1.02
(0.73
1.43
)19
026(1.1)
34(0.7)
1.10
(0.78
1.54
)991
9(1.1)
34(0.7)
N/A
983
5(1.1)
0(0.0)
History
ofan
ypsych
iatric
disorder
First-degree,nega
tive
1.00
(Ref)
131
224
8(76.3)
388
8(77.7)
1.00
(Ref)
63664
4(76.3)
362
8(78.1)
1.00
(Ref)
67560
4(76.4)
260(72.6)
First-degree,positiv
e1.29(1.211.38)
40693
5(23.7)
111
8(22.3)
1.26(1.171.35)
19811
6(23.7)
102
0(21.9)
1.74(1.382.20)
20881
9(23.6)
98(27.4)
Seco
nd-degree,nega
tive
1.00
(Ref)
36372
3(21.2)
122
5(24.5)
1.00
(Ref)
17681
6(21.2)
113
4(24.4)
1.00
(Ref)
18690
7(21.1)
91(27.4)
Seco
nd-degree,positiv
e1.06
(0.92
1.22
)10
716
5(6.2)
240(4.8)
1.09
(0.94
1.25
)52
079(6.2)
228(4.9)
0.73
(0.40
1.33
)55
086(6.2)
12(3.4)
a.Of172
489
individualsborn
inDenmark1May
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osisofan
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-
Autism spectrum disorder and anorexia nervosa
Discussion
Risk of anorexia nervosa and co-occurring ASD
We studied comorbidity and familial aggregation of anorexia nervosaand of ASD in a nationwide sample. This study corroborates earlierfindings and confirms that individuals with anorexia nervosa havea higher risk of a co-occurring ASD, and that a family history ofanorexia nervosa increases the risk for developing ASD.7,8
Similarly, individuals with ASD had an increased risk for a laterdiagnosis of anorexia nervosa and a family-member with ASDincreased the risk of developing anorexia nervosa. However, therisk of developing anorexia nervosa was also increased inindividuals with a diagnosis of major depression or anypsychiatric disorder. Moreover, the risk was also increased ifprobands had family members with any of these psychiatricdisorders. Furthermore, the study could not confirm a doseresponse effect of ASD in relatives of individuals with anorexianervosa according to the degree of shared genetic material. Hence,our results did not support the hypothesis that ASD acts as aspecific genetic or familial risk factor for developing anorexianervosa, because the risk for developing anorexia nervosa wasincreased both by the presence of ASD in probands (comorbidity)or ASD in a family-member (familial aggregation) but also thepresence of major depression or other psychiatric disordersincreased this risk. Earlier observations of an augmented risk forco-occurring anorexia nervosa and ASD in families, thus, mayexpress a non-specific genetic or familial vulnerability, whichmay also act as a risk factor for developing other psychiatricdisorders.
Familiality
This study replicates earlier findings concerning familialaggregation26 and heredity of anorexia nervosa,14 documentinga four times higher risk for developing anorexia nervosa inindividuals with a first-degree relative with anorexia nervosaand a two times higher risk of the disorder with a second-degreerelative. As expected, the doseresponse effect in relatives withASD is even stronger, which further confirms the heritability ofASD.27 These results support the good quality of the data.
ASD as a non-specific risk factor for anorexia nervosa
Several studies have demonstrated familial aggregation of majorpsychiatric disorders,28 including anorexia nervosa,26,29 in across-diagnostic perspective. Thus, familial aggregation of twoor more disorders has been demonstrated for several psychiatricdisorders, such as schizophrenia and bipolar disorder,30 Tourettesyndrome and obsessivecompulsive disorder31 and anorexianervosa and depression.1,32 Our findings, demonstrating thatASD is a non-specific familial risk factor for anorexia nervosaand vice versa, thus are in accordance with earlier findingssuggesting that psychiatric disorders in general predispose to thedevelopment of different psychiatric disorders in the offspring.33
However, the specific co-occurrence of anorexia nervosa andASD in families, has to our knowledge not been studied previouslyin a large population-based setting. Our results indicate that asimple Mendelian, genetic pathway does not explain the cross-diagnostic familial aggregation, and interactions must be morecomplex.34 The interaction between genetic and environmentalfactors may act through pleiotropy (i.e. the same genes may giverise to different disorders). Thus, a genome-wide association studyhas revealed pleiotropy in a number of psychiatric disorders,35 andsuggests that pleiotropy act through identical genes that may bemodulated by environmental factors to be expressed as various
endophenotypes,36 which again might predispose for differentpsychiatric disorders.
Comparison with findings from neuropsychologicalstudies
Neuropsychological studies, predominantly performed in adults,have reported the presence of social cognitive characteristics thatare pathognomonic of ASD in individuals with anorexia nervosaand their relatives.6,814,17 These studies suggest that at least asubgroup of individuals with anorexia nervosa demonstrate socialcognitive difficulties that may interfere with their ability to engagein family-based treatment, which is considered the treatment ofchoice for adolescents with anorexia nervosa.37,38 Most of thesestudies, however, find that the social cognitive deficits in patientswith anorexia nervosa are less severe than in patients with ASD,reporting intermediate measures of social cognitive performancebetween patients with ASD and healthy controls.11,13 None ofthese studies has included other comparison groups such aspatients and families with major depression or other psychiatricdisorders. Thus, existing data cannot conclude whether the socialcognitive deficits observed were specific to anorexia nervosa orwould also be observed in individuals with other psychiatricdisorders and in their family members. Although our results donot contradict the clinical observations; they argue for theinclusion of other pathological groups for comparison anddetermination of specificity in a cross-diagnostic perspective.
Other explanations for differences between our epidemiologicalfindings and those of clinical studies of social cognition could bethat these studies often consisted of small or selected samples andoften included a combination of individuals with different eatingdisorders, i.e. also including those with bulimia nervosa, andindividuals at different stages of the diseases.8,17 Finally, studiesmay not have accounted fully for the fact that social cognitivecharacteristics can be influenced by underweight or other neuro-biological long-term effects of anorexia nervosa; thus, time tofollow-up might have influenced the findings, because theknowledge about the impact of the duration of starvation onneuropsychological functions is limited.8,39 Moreover, manystudies differ in their definition of full recovery of anorexianervosa.40
Gender and age at onset in relation to co-occurringanorexia nervosa and ASD
Males were more frequently diagnosed with anorexia nervosabefore the age of 16 years compared with females, but they didnot more frequently have relatives with ASD or anorexia nervosa.The data presented here cannot explain this finding. This couldsimply point to the fact that males may be admitted to hospitaltreatment at younger ages than females. Two Nordic clinicalstudies have reported that males referred to hospital treatmentwere both diagnosed with anorexia nervosa at younger ages, hada shorter course of illness and had an overall more favourableprognosis than females.41,42
Males with anorexia nervosa also had a higher risk of having asecond diagnosis of ASD, but the pattern of anorexia nervosa andASD among their relatives did not indicate that genetic factorswere the explanation for this. It might be that males withunrecognised ASD first receive a diagnosis when they have contactwith the hospital system because of their eating problems. This issupported by the fact that the risk for developing ASD in themale group with anorexia nervosa was as high in the group of over16-year-olds as in the younger age group, which is in contrast to
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Koch et al
the female group with anorexia nervosa, who more often werediagnosed with ASD before the age of 16 years.
Overall, this study cannot conclude that groups defined byclinical characteristics such as gender or early-diagnosis anorexianervosa have a specifically increased risk for having ASD in thefamily, or vice versa. We are unable to determine from this studywhether anorexia nervosa and ASD are alternative gender-specificexpressions of the same genetic factor.
Strengths and limitations
We have included data from the total Danish population, whichaffords considerable statistical power, generalisability and aminimum of selection and recall bias. Hospital treatment is freeof charge in Denmark, which makes it accessible for all socio-economic groups. The Danish Civil Registration System doesnot allow people to be lost to follow-up and data are collectedprospectively for public administrative purposes and not for thisspecific study. Further strengths are the large number of cases,in particular in males, and exposed family members and theunique linkage to family members across two generations.
Our study also has limitations. One is that we were onlyconsidering categorical diagnoses rather than more richlycharacterised dimensional characteristics, which may be moresuitable for describing cross-diagnostic traits or shared endo-phenotypes or subphenotypes. Hence, we were unable to includedata on subthreshold anorectic or autistic symptoms, or onpsychological traits concerning social cognitive deficits that mayinfluence the development of anorexia nervosa and ASD, or onpatients with an intermediate phenotype between anorexianervosa and ASD. These kinds of data are not available from theregisters where only patients who reach the full diagnostic criteria(for example infantile autism) are registered. For anorexia nervosaand bulimia nervosa it is furthermore assumed that more than50% of individuals with mild to moderate disorders are neveradmitted for hospital care,43 and therefore cannot be identifiedvia the registers.
Eating disorder diagnoses in the Danish Registries are not yetsystematically validated. Register diagnoses of schizophrenia,44
childhood autism45 and depression46 have, however, been validatedand have shown good validity, and thus, diagnoses in the registriesare deemed of good quality. One study has suggested thoughthat comorbid diagnoses have less good coverage compared withthe primary diagnoses,47 potentially leading to a number ofmissing comorbid diagnoses, which may have contributed tounderestimation of the co-occurrence of anorexia nervosa and ASD.
Even though a small percentage of fathers were not identifiedat the childs birth and therefore hindered some linkages to familymembers, analysis restricted to probands, whose fathers wereknown, did not change the results; thus, this problem had a minorimpact on data quality. We decided to also include ICD-8diagnoses, to allow a larger population through the inclusion of olderbirth cohorts and mental health diagnoses of parents, even thoughthis system generated more incomplete and imprecise information,compared with ICD-10 diagnoses. Thus, inferior recognition ofpsychiatric disorders in parents may have contributed to lowerstatistical power in some of the subgroup analyses.
Summary
Our results suggest that an individual who has already developedanorexia nervosa is also at increased risk for being diagnosed withASD or vice versa. Further, we observe an aggregation of anorexianervosa and ASD in families. The risk for developing anorexianervosa, however, is equally increased if the individual hasdepression or any other psychiatric disorder, or if these disorders
are present in the family. The present data, thus, do not support aspecific genetic relationship between anorexia nervosa and ASD;however, having any psychiatric disorder or having relatives withany psychiatric disorder is a non-specific risk factor for developinganorexia nervosa. Thus, our findings are in line with recent studiesthat point to overlapping genetic liabilities for several neuro-psychiatric disorders. The risk of developing anorexia nervosashowed a doseresponse effect according to having first- andsecond-degree relatives with anorexia nervosa and supports theheritability of anorexia nervosa; likewise the heritability of ASDis confirmed. Having family members with anorexia nervosa orASD did not seem to impose a specific risk on males to developanorexia nervosa compared with females or in relation to earlyonset of anorexia nervosa.
Implications
Our results indicate that the presences of a psychiatric disordermay act as a non-specific risk factor for the development of otherpsychiatric disorder in the offspring, which further extends ourknowledge concerning the risk of mental health problems inchildren of parents with psychiatric disorders. Earlier literaturehas focused mostly on children of parents with affective disordersor psychosis,28 but children with parents with anorexia nervosaare also at elevated risk.32 Moreover, this study emphasises theimportance of dimensional and cross-diagnostic approaches toadvance our understanding of the characteristics of socialcognitive functioning in individuals with anorexia nervosa,especially when distinguishing whether these represent state ortrait characteristics and whether these putative endophenotypesare of prognostic value. Furthermore, it is important to describeco-occurrence and sequential comorbidity with other psychiatricsymptoms or disorders in anorexia nervosa illness trajectory,and to be aware of the presentation of early signs andmanifestations of the disorder that may differ somewhat betweenthe genders. Similarly, future studies should further target thepossible aetiology and impact of shared cross-diagnostic geneticliabilities, preferably in longitudinal studies. A more thoroughassessment of neuropsychological characteristics and recognitionof co-occurrence of psychiatric disorders will hopefully lead toindividually tailored treatment-courses for individuals withanorexia nervosa, which in turn may lead to a shorter course ofthe illness and improved outcome.
Susanne V. Koch, MD, PhD, Mental Health Centre for Child and AdolescentPsychiatry, Copenhagen Region and Institute of Clinical Medicine, Faculty of HealthSciences, University of Copenhagen, Copenhagen, Denmark; Janne T. Larsen, MSc,National Center for Register-based Research, School of Business and Social Sciences,University of Aarhus, Aarhus, and The Lundbeck Foundation Initiative for IntegrativePsychiatric Research, iPsych, Department of Biomedicine, Faculty of Health, AarhusUniversity, Denmark; Svend E. Mouridsen, MScPsych, Mette Bentz, MScPsych,Mental Health Centre for Child and Adolescent Psychiatry, Copenhagen Region,Denmark; Liselotte Petersen, MSc, PhD, National Center for Register-basedResearch, School of Business and Social Sciences, University of Aarhus, Aarhus,iPsych, Department of Biomedicine, Faculty of Health, Aarhus University, and TheLundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark;Cynthia Bulik, PhD, FAED, Department of Psychiatry, University of North Carolina,Chapel Hill, North Carolina, USA, and Department of Medical Epidemiology andBiostatistics, Karolinska Institutet, Stockholm, Sweden; Preben B. Mortensen, MD,DMSci, National Center for Register-based Research, School of Business and SocialSciences, University of Aarhus, Aarhus, and The Lundbeck Foundation Initiative forIntegrative Psychiatric Research, iPsych, Department of Biomedicine, Faculty ofHealth, Aarhus University, Denmark; Kerstin J. Plessen, MD, PhD, Mental HealthCentre for Child and Adolescent Psychiatry, Copenhagen Region and Institute ofClinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen,Denmark
Correspondence: Susanne V. Koch, Mental Health Centre for Child andAdolescent Psychiatry, University of Copenhagen, Lers Parkalle 107, lth, DK2100, Copenhagen, Denmark. Email: [email protected]
First received 23 Jun 2014, accepted 21 Aug 2014
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Autism spectrum disorder and anorexia nervosa
Funding
Mental Health Services, Capital Region, Copenhagen, Denmark.
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10.1192/bjp.bp.114.153221Access the most recent version at DOI: 2015, 206:401-407.BJP
Preben B. Mortensen and Kerstin J. PlessenSusanne V. Koch, Janne T. Larsen, Svend E. Mouridsen, Mette Bentz, Liselotte Petersen, Cynthia Bulik,register-based cohort-study
nationwideand in their first- and second-degree relatives: Danish Autism spectrum disorder in individuals with anorexia nervosa
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