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Study Report
Reference | Ilott NE, 201021122117 |
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Citation | Ilott N. E., Saudino K. J. and Asherson P. (2010) "Genetic influences on attention deficit hyperactivity disorder symptoms from age 2 to 3: a quantitative and molecular genetic investigation." BMC Psychiatry, 10: 102. |
Study Design | twin study |
Study Type | Candidate-gene association study |
Sample Size | 312 same-sex pairs of twins (144 MZ, 168 DZ; 164 male pairs, 148 female pairs) |
Predominant Ethnicity | Caucasian |
Population | USA |
Gender | 164 male pairs, 148 female pairs |
Age Group | Children/Adolescents : 2-3 years |
Summary | A tw in study design was used to assess the degree to which additive genetic variance influences ADHD symptom scores across two ages during infancy. A further objective in the study was to observe whether genetic association with a number of candidate markers reflects results from the quantitative genetic analysis. They have studied 312 twin pairs at two time-points, age 2 and age 3. A composite measure of ADHD symptoms from two parent-rating scales: The Child Behavior Checklist/1.5-5 years (CBCL) hyperactivity scale and the Revised Rutter Parent Scale for Preschool Children (RRPSPC) was used for both quantitative and molecular genetic analyses. At ages 2 and 3 ADHD symptoms are highly heritable (h2 = 0.79 and 0.78, respectively) with a high level of genetic stability across these ages. However, they also observe a significant level of genetic change from age 2 to age 3. There are modest influences of non-shared environment at each age independently (e2 = 0.22 and 0.21, respectively), with these influences being largely age-specific. In addition, they find modest association signals in DAT1 and NET1 at both ages, along with suggestive specific effects of 5-HTT and DRD4 at age 3. ADHD symptoms are heritable at ages 2 and 3. Additive genetic variance is largely shared across these ages, although there are significant new effects emerging at age 3. Results from this genetic association analysis reflect these levels of stability and change and, more generally, suggest a requirement for consideration of age-specific genotypic effects in future molecular studies. |
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Total Sample | The present analyses include 312 same-sex pairs of twins (144 MZ, 168 DZ; 164 male pairs, 148 female pairs). Although the sample was predominately Caucasian (85.4%), ethnicity was generally representative of the Massachusetts population (3.2% Black, 2% Asian, 7.3% Mixed, 2.2% Other). Socioeconomic status according to the Hollingshead Four Factor Index (1975) ranged from low to upper middle class (range = 20.5-66; M = 50.9, SD = 14.1). |
Sample Collection | 85.4% Caucasian, 3.2% Black, 2% Asian, 7.3% Mixed, 2.2% Other |
Diagnosis Description | A composite measure of ADHD symptoms from two parent-rating scales: The Child Behavior Checklist/1.5 - 5 years (CBCL) hyperactivity scale and the Revised Rutter Parent Scale for Preschool Children (RRPSPC). Twins were selected preferentially for higher birth weight and gestational age. No twins with birth weights below 1750 grams or with gestational ages less than 34 weeks were included in the study. Twins were also excluded if one or both twins had a health problem that might affect motor activity (e.g., cerebral palsy, club foot) or had chromosomal abnormalities. |
Technique | Residualised scores were used for all model fitting procedures. Both parents and offspring were genotyped. VNTR polymorphisms (DRD4 exon 3, DAT1 3' UTR, DAT1 intron 8, the 5-HTTLPR and MAOA promoter) were genotyped in-house. Single nucleotide polymorphisms (SNPs) were genotyped by Prevention. |
Analysis Method | Tests of allelic association were performed using the Quantitative Transmission Disequilibrium Test (QTDT) on ADHD scores residualised for sex effects. Three models of association were tested using a likelihood ratio test implemented in QTDT: the 'Total Association' test (AT), the 'Within-Test' of association (AW) and the test of stratification (AP). |
Result Description | At ages 2 and 3 ADHD symptoms are highly heritable with a high level of genetic stability across these ages. However, they also observe a significant level of genetic change from age 2 to age 3. There are modest influences of non-shared environment at each age independently, with these influences being largely age-specific. In addition, they find modest association signals in DAT1 and NET1 at both ages, along with suggestive specific effects of 5-HTT and DRD4 at age 3. |
SNP | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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rs6323 | QTDT AW P-value=0.31, X2=1.03, df=1 at age 2; QTDT AW P-value=0.83, X2=0.97, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs6039806 | QTDT AT P-value=0.96, X2=0, df=1, QTDT AW P-value=0.99, X2=0, df=1 at age 2; QTDT AT P-value=0.97, X2=0.08, df=1, QTDT AW P-value=0.52, X2=0.41, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs998424 | QTDT AT P-value=0.07, X2=3.3, df=1, QTDT AW P-value=0.04, X2=4.42, df=1 at age 2; QTDT AT P-value=0.59, X2=0.83, df=1, QTDT AW P-value=0.07, X2=3.22, df=1 at age 3 | modest, nominally significant associations in the AW test at...... modest, nominally significant associations in the AW test at age 2 More... | Significant | ||
rs1051312 | QTDT AT P-value=0.43, X2=0.63, df=1, QTDT AW P-value=0.85, X2=0.04, df=1 at age 2; QTDT AT P-value=0.58, X2=0, df=1, QTDT AW P-value=0.42, X2=0.65, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs11080121 | QTDT AT P-value=0.14, X2=2.16, df=1, QTDT AW P-value=0.1, X2=2.71, df=1 at age 2; QTDT AT P-value=0.23, X2=0.12, df=1, QTDT AW P-value=0.03, X2=4.77, df=1 at age 3 | modest, nominally significant associations in the AW test at...... modest, nominally significant associations in the AW test at age 3 More... | Significant | ||
rs11564750 | QTDT AT P-value=0.8, X2=0.06, df=1, QTDT AW P-value=0.39, X2=0.75, df=1 at age 2; QTDT AT P-value=0.43, X2=0.14, df=1, QTDT AW P-value=0.94, X2=0.01, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs11568324 | QTDT AT P-value=0.04, X2=4.38, df=1, at age 2; QTDT AT P-value=0.13, X2=0.58, df=1, at age 3 | modest, nominally significant associations in the AT test at...... modest, nominally significant associations in the AT test at age 2 More... | Significant | ||
rs140701 | QTDT AT P-value=0.09, X2=2.96, df=1, QTDT AW P-value=0.08, X2=3.03, df=1 at age 2; QTDT AT P-value=0.38, X2=0, df=1, QTDT AW P-value=0.07, X2=3.24, df=1 at age 3 | modest, nominally significant associations in the AW test at...... modest, nominally significant associations in the AW test at age 3 More... | Non-significant | ||
rs2020936 | QTDT AT P-value=0.27, X2=1.24, df=1, QTDT AW P-value=0.17, X2=1.92, df=1 at age 2; QTDT AT P-value=0.4, X2=1.34, df=1, QTDT AW P-value=0.27, X2=1.2, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs2066713 | QTDT AT P-value=0.84, X2=0.04, df=1, QTDT AW P-value=1, X2=0, df=11 at age 2; QTDT AT P-value=0.5, X2=1.27, df=1, QTDT AW P-value=0.57, X2=0.32, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs2242447 | QTDT AT P-value=0.27, X2=1.23, df=1, QTDT AW P-value=0.31, X2=1.03, df=1 at age 2; QTDT AT P-value=0.18, X2=3.56, df=1, QTDT AW P-value=0.16, X2=2.01, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs2550946 | QTDT AT P-value=0.51, X2=0.43, df=1, QTDT AW P-value=0.4, X2=0.71, df=1 at age 2; QTDT AT P-value=0.47, X2=0.16, df=1, QTDT AW P-value=0.32, X2=0.99, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs362987 | QTDT AT P-value=0.84, X2=0.04, df=1, QTDT AW P-value=0.79, X2=0.07, df=1 at age 2; QTDT AT P-value=0.91, X2=0.04, df=1, QTDT AW P-value=0.39, X2=0.39, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs3746544 | QTDT AT P-value=0.83, X2=0.05, df=1, QTDT AW P-value=0.67, X2=0.18, df=1 at age 2; QTDT AT P-value=0.21, X2=1.75, df=1, QTDT AW P-value=0.16, X2=1.98, df=1 at age 3 | no significant association no significant association | Non-significant | ||
rs3785157 | QTDT AT P-value=0.06, X2=3.68, df=1, QTDT AW P-value=0.03, X2=4.65, df=1 at age 2; QTDT AT P-value=0.48, X2=0.37, df=1, QTDT AW P-value=0.04, X2=4.3, df=1 at age 3 | modest, nominally significant associations in the AW test at...... modest, nominally significant associations in the AW test at ages 2 and 3 More... | Significant |
Variant Name | Allele Change | Risk Allele | Statistical Values | Author Comments | Result of Statistical Analysis |
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MAOA promoter VNTR | QTDT AW P-value=0.2, X2=4.68, df=3 at age 2; QTDT...... QTDT AW P-value=0.2, X2=4.68, df=3 at age 2; QTDT AW P-value=0.81, X2=0.05, df=3 at age 3 More... | no significant association | Non-significant | ||
DRD4 exon3 VNTR | QTDT AT P-value=0.19, X2=4.74, df=3, QTDT AW P-va...... QTDT AT P-value=0.19, X2=4.74, df=3, QTDT AW P-value=0.35, X2=3.26, df=3 at age 2; QTDT AT P-value=0.05, X2=7.82, df=3, QTDT AW P-value=0.03, X2=8.69, df=3 at age 3 More... | modest, nominally significant associations in the AT and AW tests at age 3 | Significant | ||
5HTTLPR | short/long | QTDT AT P-value=0.57, X2=0.31, df=1, QTDT AW P-va...... QTDT AT P-value=0.57, X2=0.31, df=1, QTDT AW P-value=0.87, X2=0.03, df=1 at age 2; QTDT AT P value=0.87, X2=0.03, df=1, QTDT AW P-value=0.34, X2=0.91, df=1 at age 3 More... | no significant association | Non-significant | |
SLC6A3 3'-UTR VNTR | QTDT AT P-value=0.03, X2=7, df=2, QTDT AW P-value...... QTDT AT P-value=0.03, X2=7, df=2, QTDT AW P-value=0.08, X2=5.09, df=2 at age 2; QTDT AT P-value=0.004, X2=11.15, df=2, QTDT AW P-value=0.002, X2=12.17, df=2 at age 3 More... | modest, nominally significant associations in the AT test at age 2, and in the AT and AW tests at age 3, and still significant after bonferroni correction in the AW test at age 3 | Significant | ||
SLC6A3 intron8 VNTR | QTDT AT P-value=0.18, X2=3.42, df=2, QTDT AW P-va...... QTDT AT P-value=0.18, X2=3.42, df=2, QTDT AW P-value=0.24, X2=2.84, df=2 at age 2; QTDT AT P-value=0.24, X2=2.9, df=2, QTDT AW P-value=0.2, X2=3.21, df=2 at age 3 More... | no significant association | Non-significant |
Gene | Statistical Values/Author Comments | Result of Statistical Analysis |
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SNAP25 | no SNP showed modest, nominally significant association no SNP showed modest, nominally significant association | Non-significant |
MAOA | no SNP showed modest, nominally significant association no SNP showed modest, nominally significant association | Non-significant |
SLC6A3 | 1 SNP showed modest, nominally significant association in th...... 1 SNP showed modest, nominally significant association in the AT tests at ages 2 and 3 More... | Significant |
SLC6A4 | 2 SNPs showed modest, nominally significant association in t...... 2 SNPs showed modest, nominally significant association in the AW tests at age 3 More... | Significant |
SLC6A2 | 2 SNPs showed modest, nominally significant association in t...... 2 SNPs showed modest, nominally significant association in the AT and AW tests at age 2, and 1 SNP showed modest, nominally significant association in the AW tests at ages 2 and 3 More... | Significant |
DRD4 | 1 SNP showed modest, nominally significant association in th...... 1 SNP showed modest, nominally significant association in the AT and AW tests at age 3 More... | Significant |
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Last update: Feb 26, 2014