University of Groningen
Gene-environment interactions on the course of Attention-Deficit/Hyperactivity Disorder
(ADHD) symptoms
Brinksma, Djûke Maaike
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Brinksma, D. M. (2018). Gene-environment interactions on the course of Attention-Deficit/Hyperactivity
Disorder (ADHD) symptoms: From early into late adolescence. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
129
S
Supplementary Information 2.1
Genotyping Length Polymorphisms of DRD4, 5-HTTLPR, and MAOA. Genotyping of
the length polymorphisms (LP) DRD4, HTTLPR, and SNP rs25331 (A/G SNP in L HTTLPR)
and MAOA was done at the Research lab for Multifactorial Diseases within the Human
Genetics department of the Radboud University Nijmegen Medical Centre in Nijmegen,
The Netherlands.
The 48-bp direct repeat polymorphism in exon 3 of DRD4 was genotyped on the
Il-lumina BeadStation 500 platform (IlIl-lumina). Three percent blanks as well as duplicates
between plates were taken along as quality controls during genotyping. Determination
of the length of the alleles was performed by direct analysis on an automated capillary
sequencer (ABI3730, Applied Biosystems, Nieuwerkerk a/d IJssel, The Netherlands) using
standard conditions. Call rate for DRD4 was 99.4%.
Genotyping of the HTTLPR polymorphism in the promoter region of SLC6A4 (5-HTT,
SERT) gene was performed by simple sequence length analysis. Call rate was 91.6%. A
custom-made TaqMan assay (Applied Biosystems) was utilized to genotype the single
nucleotide substitution (A to G), which is present in the HTTLPR long (l) allele (rs25531).
Call rate was 96.5%. Concordance between DNA replicates showed an accuracy of 100%.
All lg alleles were recoded into s’, because it has been shown that this polymorphism
represents low serotonin expression comparable to the s’ allele, while la was recoded
as l’. The 30bp variable number of tandem repeat polymorphism (called MAOA-LPR or
MAOA-uVNTR) was also genotyped on the Illumina BeadStation 500 platform. Three
percent blanks as well as duplicates between plates were taken along as quality controls
during genotyping. Call rate was 100% for MAOA. All polymorphisms were well within
Hardy-Weinberg equilibrium (HWE p-values ranged from 0.77 to 0.87).
Genotyping of DRD2, and Catechol-O-Methyltransferase (COMT). The DRD2 TaqIA
(rs1800497), and the COMT val158met (rs4680) were genotyped by the Golden Gate
Illumina BeadStation 500 platform (Illumina Inc., San Diego, CA) according to the
manu-facturers protocol. Call rates were 100% for DRD2 and 95% for COMT. All DNA samples
could be amplified, and concordance between DNA replicates (n = 53) showed 100%
genotyping accuracy (Nederhof et al., 2010). Both SNPs were well within
Hardy–Wein-berg equilibrium.
130
Supplementary Information 2.2
Two-way interactions between pre- and perinatal factors × time during the course of attention-deficit/hyperac-tivity disorder (ADHD) symptoms across adolescencea
Parameter Estimateb SEb p Interceptc 413.99 27.69 <.001 Time -23.93 3.67 <.001 MSDPd 125.20 26.51 <.001 MDDPd -10.31 29.34 .718 PDCse 97.88 24.98 <.001 LBWf 9.72 81.50 .905 MSDPd*Time -6.13 3.20 .055 MDDPd*Time -3.32 3.44 .334 PDCse*Time -8.10 2.95 .006 LBWf*Time -8.90 9.76 .362
Note. MSDP=Maternal smoking during pregnancy; MDDP=Maternal drinking during pregnancy;
PDCs=Index of pregnancy and delivery complications; LBW=Low birth weight
aAdjusted for sex and ADHD medication bValues multiplied by 1000 to increase readability
cSignificant variability (p < .001) in intercept for ADHD symptoms, var(u0j)=197.95, χ²(1)=22.23 dMSDP and MDDP coded as no (0), mild (1), or moderate (2)
ePDCs coded as no (0), few (1), or many (2) fLBW coded as yes (0) or no (1).
Supplementary Information 2.3
Attention-deficit/hyperactivity disorder (ADHD) symptom levels plotted for different levels of an index score of pregnancy and delivery complications across T1 (M = 11.1 yrs), T2 (M = 13.4 yrs), and T3 (M = 16.2 yrs).
Supplementary Information 2.3
131
S
Supplementary Information 2.4
Three-way interactions for the MAOA gene × pre- and perinatal factors × time during the course of ADHD symp-toms across adolescence for boys onlya
Parameter Estimateb SEb p Interceptc 610.31 42.06 <.001 Time -32.95 6.37 <.001 MAOAd -118.29 48.36 .015 MSDPe 90.03 45.96 .050 MDDPe -20.80 50.31 .679 PDCsf 70.99 39.34 .071 LBWg 459.56 132.00 .001 Genotyped*Time 5.01 7.27 .491 MSDPe*Time -6.14 6.79 .366 MDDPe*Time -11.01 7.70 .153 PDCsf*Time -8.34 5.98 .163 LBWg*Time -7.28 2.06 <.001 MAOAd*MSDPe*Time -2.97 7.65 .698 MAOAd*MDDPe*Time 11.04 8.52 .196 MAOAd*PDCsf*Time 0.40 6.81 .953 MAOAd*LBWg*Time 82.87 23.30 <.001
Note. MSDP=Maternal smoking during pregnancy; MDDP=Maternal drinking during pregnancy;
PDCs=Index of pregnancy and delivery complications; LBW=Low birth weight, see further Table 1.
aAdjusted ADHD medication
bValues multiplied by 1000 to increase readability
cSignificant variability (p < .001) in intercept for ADHD symptoms (var(u
0j)=206.11, χ²(1)=22.30) dMAOA as low (0) or high activity (1)
eMSDP and MDDP coded as no (0), mild (1), or moderate (2) fPDCs coded as no (0), few (1), or many (2)
132
Supplementary Information 4.1
The Long-Term Difficulties Questionnaire: This questionnaire was filled in by the
partici-pants’ parents with the instruction to indicate which (long-term) difficulties the adolescents
had been exposed to during the past two years.
Life stressors
Person-related life stressors
Chronic illnesses or physical handicaps of the child
High work pressure at school
Lack of friends
Being bullied
Long-lasting conflicts of self with a family member
Long-lasting conflicts of self with others
Environment-related life stressors
Chronic illnesses or physical handicaps of a family member
Housing problems
Neighborhood problems, such as violence or discrimination
Financial problems
133
S
Su
pp
le
m
en
ta
ry
In
fo
rm
at
io
n
5.
1
Sample char ac teristic s p er DRD4 (n = 1,848) and 5-HT TLPR (n = 1,763) status DRD4 genot yp e 5-HT TLP R genot yp e 7-rep ea t absent n = 1,167 (63.1%) 7-rep ea t present n = 681 (36.9%) Test st atistic SS n = 452 (25.6%) LS n = 871 (49.4%) LL n = 440 (25.0%) Test st atistic P opula tion-based c ohor t (%) 890 (76.3%) 536 (78.7%) χ²(1) = 1.46 338 (24.3%) 696 (50.1%) 355 (25.6%) χ²(2) = 5.95 A ge in y ears , M (SD ) T1 11.09 (.53) 11.09 (.57) F(1) = 0.04 11.07 (.54) 11.09 (.54) 11.09 (.55) F(2) = 0.19 T2 13.35 (.62) 13.38 (.61) F(1) = 0.74 13.34 (.63) 13.39 (.61) 13.36 (.60) F(2) = 0.80 T3 16.15 (.68) 16.17 (.69) F(1) = 0.17 16.15 (.69) 16.18 (.68) 16.15 (.70) F(2) = 0.37 M ale gender (%) 581 (49.8%) 375 (55.1%) χ²(1) = 4.80* 246 (54.4%) 435 (50.0%) 221 (50.0%) χ²(2) = 2.60 ADHD medica tion use a, N (%) T1 134 (11.5%) 62 (9.1%) χ²(1) = 2.57 49 (10.8%) 99 (11.3%) 34 (7.7%) χ²(2) = 4.36 T2 151 (12.9%) 71 (10.4%) χ²(1) = 2.57 51 (11.3%) 106 (12.2%) 45 (10.2%) χ²(2) = 1.11 T3 116 (9.9%) 55 (8.1%) χ²(1) = 1.78 39 (8.6%) 84 (9.6%) 31 (7.0%) χ²(2) = 2.49 Main v ariables ADHD sympt oms b,e, M (SD ) T1 0.69 (.53) 0.67 (.52) F(1) = 0.30 0.73 (.54) 0.66 (.53) 0.66 (.49) F(2) = 2.57 T2 0.54 (.50) 0.54 (.48) F(1) = 0.26 0.57 (.50) 0.52 (.50) 0.52 (.46) F(2) = 1.49 T3 0.49 (.47) 0.47 (.42) F(1) = 1.13 0.51 (.47) 0.48 (.46) 0.45 (.43) F(2) = 1.69 F amily clima te c,d , M (SD ) T1 1.79 (.37) 1.80 (.37) F(1) = 0.15 1.81 (.38) 1.80 (.38) 1.78 (.36) F(2) = 0.75 T2 1.68 (.41) 1.67 (.42) F(1) = 0.18 1.68 (.43) 1.68 (.41) 1.66 (.40) F(2) = 0.50 T3 1.66 (.41) 1.69 (.42) F(1) = 1.61 1.70 (.42) 1.68 (.42) 1.62 (.39) F(2) = 3.63* S chool clima te c,e, M (SD ) T1 2.28 (.69) 2.28 (.70) F(1) = 0.06 2.27 (.69) 2.29 (.70) 2.28 (.72) F(2) = 0.22 T2 2.37 (.61) 2.39 (.60) F(1) = 0.49 2.38 (.60) 2.38 (.59) 2.35 (.63) F(2) = 0.31 T3 2.50 (.57) 2.51 (.56) F(1) = 0.07 2.54 (.56) 2.61 (.57) 2.46 (.57) F(2) = 2.05 Not e. DRD4 = D opamine D4 R ec ept or G ene ADHD = A tt en tion-D eficit/H yper ac tivit y Disor der * p < .05, ** p <.01, *** p < .001 a M eth ylphenida te , de xamphetamine and a tomo xetine use a t an y time during the past y
ear (1) v ersus non-use (0) b M ean of 7-it ems DSM -IV -or ien
ted ADHD subscale of the CBCL (
Achenbach, 1991; sc or e r ange 0-2) c T1-T2 < T2-T3 a t p < .001. d M ean of 12-it em F amily F unc
tioning scale of the F
AD (Epst ein et al ., 1983; sc or e r ange 0-4) e M ean of 7 selec ted it ems of the t
eacher and classma
tes subscales of the S
ocial P roduc tion F unc tions (SPF ; Or mel et al ., 1997, Or mel , 2002; sc or e r ange 0-5).
134
Supplementary Information 5.2
Standardized path coefficients of within-person level from the random intercept cross-lagged panel model for the associations between ADHD symptoms and family and school climate across adolescence while controlling for ADHD medication at all time points.
Supplementary Information 5.2
Note. ADHD = Attention-Deficit/Hyperactivity Disorder.
Left, and right path coefficients represent absences (n = 1,167), and presence 7-repeat variant (n = 681) of the DRD4 genotype, respectively.
*p < .05, **p < .01, and ***p < .001 indicate significant path coefficients within the respective variation of the DRD4.
135
S
Supplementary Information 5.3
Standardized path coefficients of within-person level from the random intercept cross-lagged panel model for the associations between ADHD symptoms and family and school climate across adolescence while controlling for ADHD medication at all time points.
Supplementary Information 5.3
Note. ADHD = Attention-Deficit/Hyperactivity Disorder.
Left, middle, and right path coefficients represent S-allele homozygotes (n = 452), L-allele heterozygotes (n = 871), and L-allele homozygotes (n = 440) of the 5-HTTLPR genotype, respectively.
*p < .05, **p < .01, and ***p < .001 indicate significant path coefficients within the respective variation of the 5-HTTLPR.
