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Journal of Psychiatry & Neuroscience : JPN logoLink to Journal of Psychiatry & Neuroscience : JPN
. 2012 Jan;37(1):46–52. doi: 10.1503/jpn.100173

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder

Ke-Sheng Wang 1,✉, Xuefeng Liu 1, Qunyuan Zhang 1, Nagesh Aragam 1, Yue Pan 1
PMCID: PMC3244498  PMID: 21651830

Abstract

Background

Previous studies have suggested that there may be a parent-of-origin effect for attention-deficit/hyperactivity disorder (ADHD) candidate genes. The objective of the present study was to investigate parent-of-origin effects using a genome-wide association analysis of the International Multicentre ADHD Genetics (IMAGE) study sample.

Methods

Family-based association analysis for ADHD using 846 ADHD probands and their parents was performed using the PLINK program, and parent-of-origin effects were studied using a Z score for the difference in paternal versus maternal odds ratios.

Results

We identified 44 single nucleotide polymorphisms (SNPs) showing parent-of-origin effects at a significance level of p < 0.001. The most significant SNP, rs7614907, is at position 3q13.33 in the CDGAP gene (p = 0.000064 for parent-of-origin effect). Furthermore, 2 genes (FAS and PDLIM1) showed moderate parent-of-origin effects (p = 0.00086 for rs9658691 and p = 0.00077 for rs11188249) and strong maternal transmission (p = 0.000059 for rs9658691 and p = 0.0000068 for rs11188249). In addition, ZNF775 showed a moderate parent-of-origin effect (p = 0.00036 for rs7790549) and strong paternal transmission (p = 0.000041 for rs7790549).

Limitations

We only had 1 sample available for analysis.

Conclusion

These results suggest several genes or regions with moderate parent-of-origin effects, and these findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable childhood-onset psychiatric disorder affecting 2%–6% of children worldwide and is characterized by developmentally inappropriate levels of inattention, hyper-activity and impulsivity. A previous review of genetic epidemiologic studies, including more than 14 published twin studies and 5 adoption studies, indicated that most of the variation was attributable to genetic factors, consistently demonstrating high heritability in the range of 75%–91%.1 Recent reviews further showed that twin studies of ADHD had been consistent with an average heritability rate of 76%.2–5

Previous studies have suggested that there may be a parent-of-origin effect for ADHD candidate genes. For example, a generalized parent-of-origin effect was observed in an Irish ADHD study.6 Furthermore, gene-specific parent-of-origin effects have been observed for BDNF,7 DAT1 (SLC6A3),8 DDC,9,10 GNAL,11 HTR1B,12 SLC6A2,10 SLC6A4,6,13 SNAP25,14,15 TPH2, DRD4, DRD5 and SLC6A3,6 FADS2 and ADRBK2.10 Several studies have failed to confirm an overall parent-of-origin effect;10,15,16 however, gene-specific parent-of-origin effects cannot be excluded.10

The conventional genome-wide association (GWA) study approach is a hypothesis-free, systematic search of tagging single nucleotide polymorphisms (SNPs) across the genome to identify novel associations with common diseases. It has emerged as a powerful tool to identify disease-related genes for many common human disorders and other phenotypes.17 Recently, several GWA studies of ADHD and related phenotypes were reported, and 4 of them were based on a sample set of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN).18 For example, the first GWA scan of ADHD was completed on a sample of 909 complete proband–parent trios with a child with the combined subtype of ADHD from the IMAGE project.19 To our knowledge, an examination of parent-of-origin effects in a GWA study of ADHD has not been undertaken. Therefore, we conducted a GWA analysis of ADHD to search for genetic variants showing the difference in transmission frequency between paternal and maternal alleles.

Methods

Study sample

Families were collected for the IMAGE project. A total of 924 affected proband–parent trios were initially selected for the GWA scan. Family members were primarily of Western European origin, hailing from 8 countries: Belgium, Germany, Ireland, Israel, the Netherlands, Spain, Switzerland and the United Kingdom. To reduce the genetic heterogeneity, we chose 846 probands initially ascertained to have DSM-IV20 combined subtype ADHD. Demographic and clinical characteristics of these participants have been described elsewhere.19 Genotyping data using the Perlegen (600K) genome-wide association platform (599 164 SNPs) were available for these 846 probands and their parents.

Assessment of Hardy–Weinberg equilibrium

We tested departure from the Hardy–Weinberg equilibrium for unaffected founders using PLINK version 1.07,21 and we also estimated the genotype call rate and minor allele frequency (MAF).

Family-based association analyses

Family-based association studies, such as the transmission disequilibrium test (TDT), are preferable to case–control studies of allelic association when there is population admixture.22 In this study, family-based association analysis (i.e., TDT) for ADHD was performed using PLINK. We studied the parent-of-origin effect using the Z score to assess the difference in paternal versus maternal odds ratios in PLINK.

Multiple testing

For statistical significance of parent-of-origin effects, we used a conservative per test significance level of α = 0.0000005.17 At the same time, we also used a less stringent criterion of “suggestive association” with a cut-off of α = 0.001. In addition to obtaining nominal p values, empirical p values were generated by 100 000 permutation tests using a Max (T) permutation procedure implemented in PLINK. In this procedure, 2 sets of empirical significance values were calculated: point-wise estimates of an individual SNP’s significance (empirical pointwise p values) and corrected values for multiple testing (corrected empirical p values).

Haplotype block and fine-mapping

We assessed pairwise linkage disequilibrium statistics (D′) for unrelated founders using Haploview.23 We identified haplotype blocks, within which SNPs have strong linkage disequilibrium (D′ > 0.8), for interesting candidate genes or regions. Then we chose several SNPs within blocks, including the associated SNPs in the IMAGE data. Haplotype analysis based on a sliding window of fixed haplotype size was performed using the TDTPHASE program in UNPHASED version 2.404.24 We performed a Fisher exact test in SAS version 9.2 based on a 2 × 2 contingency test (χ2 test) to evaluate the difference in transmission frequency between paternal and maternal haplotypes (parent-of-origin effect).

Results

Genotype quality control

We removed SNPs with the Hardy–Weinberg equilibrium of p < 0.0001, with call rates less than 95% or with an MAF less than 5%. There were 491 705 SNPs left for further analysis.

Genome-wide association analysis

In total, we identified 44 SNPs showing parent-of-origin effects with p < 0.001, and 22 of them were located within 19 genes (Table 1). A more comprehensive list of SNPs (all 44 showing parent-of-origin effects) with p < 0.001 is presented in Appendix 1 (Table S1), available at www.cma.ca/jpn. The most significant SNP, rs7614907, was at position 3q13.33 in CDGAP (p = 0.000064). Two SNPs in SLC4A4 (rs1452898 and rs7673301), 2 in NXN (rs2644700 and rs6042229) and 2 in STARD13 (rs10492402 and rs7322586) showed parent-of-origin effects. In addition, SNPs in AK5, HLA-DOA, TAAR9, TAAR6, NKAINS, FAS and PDLIM1 showed parent-of-origin effects.

Table 1.

Twenty-two single nucleotide polymorphisms within genes showing parent-of-origin effects with p < 0.001

Chr. SNP database Base pair position* Known gene GT AF All transmissions Maternal Paternal Parent-of-origin effect
T/NT χ2† p T/NT χ2 p T/NT χ2 p χ2‡ Z§ p Point. p** Corr. p††
1 rs17098286 77640412 AK5 G/C 0.08 120/103 1.30 0.26 45/62 2.73 0.099 76/42 9.88 0.0017 11.28 3.34 0.00083 0.00028 0.011
1 rs542494 232490912 SLC35F3 C/T 0.15 206/203 0.02 0.88 120/80 8.00 0.0047 86/123 6.55 0.01 14.53 3.79 0.00015 0.00002 0.0014
3 rs7614907 120559179 CDGAP T/C 0.05 83/68 1.49 0.22 26/43 4.70 0.030 58/25 13.3 0.00027 15.80 4.00 0.000064 0.00004 0.00053
4 rs1452898 72359433 SLC4A4 C/A 0.14 180/200 1.05 0.30 73/119 11.0 0.00090 107/81 3.60 0.058 13.61 3.67 0.00025 0.00006 0.0025
4 rs7673301 72406891 SLC4A4 T/C 0.12 157/173 0.78 0.38 61/101 9.94 0.0016 97/73 3.41 0.065 12.52 3.53 0.00042 0.00008 0.0051
4 rs17484427 115089316 ARSJ G/C 0.15 216/211 0.06 0.809 90/123 5.10 0.023 126/88 6.75 0.0094 11.80 3.42 0.00063 0.00014 0.0081
6 rs2582 33082529 HLA-DOA T/G 0.13 207/190 0.73 0.39 90/117 3.52 0.061 117/73 10.2 0.0014 13.01 3.59 0.00034 0.00002 0.0037
6 rs9389004 132901953 TAAR9 A/G 0.05 79/66 1.17 0.28 34/47 2.11 0.14 46/20 10.4 0.0013 11.27 3.33 0.00087 0.00043 0.012
6 rs8192624 132933946 TAAR6 A/G 0.08 128/125 0.04 0.85 51/76 4.96 0.026 78/50 6.17 0.013 11.01 3.31 0.00094 0.00042 0.013
7 rs7790549 149720965 ZNF775 A/G 0.08 143/109 4.59 0.032 67/76 0.57 0.45 77/34 16.8 0.000041 12.90 3.57 0.00036 0.00005 0.004
8 rs12114607 63416967 NKAIN3 A/G 0.13 180/173 0.14 0.71 109/73 7.12 0.0076 71/100 4.92 0.027 11.90 3.43 0.0006 0.00006 0.0077
8 rs13255144 119516196 SAMD12 T/C 0.35 373/409 1.66 0.20 167/233 11.2 0.00081 206/175 2.52 0.11 11.87 3.47 0.00052 0.00002 0.0064
10 rs9658691 90746143 FAS C/T 0.10 128/169 5.66 0.017 53/103 16.1 0.00059 76/67 0.57 0.45 11.18 3.33 0.00086 0.00011 0.012
10 rs11188249 97000369 PDLIM1 G/A 0.10 122/174 9.14 0.0025 45/99 20.3 0.0000068 77/75 0.03 0.87 11.50 3.37 0.00077 0.0002 0.010
13 rs10492402 32606789 STARD13 T/C 0.07 108/111 0.04 0.83 44/72 6.75 0.0093 64/39 6.07 0.014 12.79 3.54 0.00041 0.00025 0.0049
13 rs7322586 32610785 STARD13 A/G 0.07 110/110 0.01 1.00 44/70 5.93 0.015 66/40 6.37 0.012 12.31 3.47 0.00051 0.00024 0.0063
15 rs4777414 69675927 THSD4 C/T 0.10 159/140 1.21 0.27 92/53 10.6 0.0012 68/88 2.58 0.10 11.90 3.44 0.00059 0.0002 0.0074
16 rs4412964 82113739 CDH13 T/C 0.37 359/376 0.39 0.53 197/157 4.53 0.033 163/219 8.51 0.0035 12.39 3.55 0.00039 0.00001 0.0046
17 rs2644700 729799 NXN T/C 0.09 116/140 2.25 0.13 70/54 2.07 0.15 46/86 12.1 0.00050 12.04 3.44 0.00058 0.0002 0.0073
17 rs604229 733578 NXN T/C 0.08 101/123 2.17 0.14 65/49 2.27 0.13 37/75 13.0 0.00031 13.12 3.60 0.00032 0.00013 0.0034
18 rs1452643 29741426 NOL4 T/A 0.19 236/244 0.13 0.72 91/131 7.21 0.0073 145/113 3.97 0.046 11.05 3.31 0.00093 0.00012 0.013
19 rs17325700 38923667 CHST8 T/A 0.10 149/145 0.05 0.82 60/88 5.33 0.021 90/58 6.97 0.0083 12.16 3.48 0.00051 0.00011 0.0063
Open in a new tab

AF = minor allele frequency of the SNP in founders; Chr. = chromosome; GT = genotype for the SNP; SNP = single nucleotide polymorphism; T/NT = transmitted/nontransmitted allele.

*

Physical position is based on NCBI Genome Build 36.3.

†

χ2 transmission disequilibrium test statistic.

‡

χ2 based on a 2 × 2 contingency test to evaluate the difference in transmission frequency between paternal and maternal haplotypes.

§

Z score for difference in paternal versus maternal odds ratios.

Nominal p value, asymptotic for parent-of-origin test.

**

Empirical pointwise p value, computed by 100 000 permutation tests using a Max (T) permutation procedure implemented in PLINK.

††

Empirical p value corrected for multiple testing, generated by 100 000 permutation tests using a Max (T) permutation procedure implemented in PLINK.

Table 1 showed that only 3 of 22 SNPs (rs7790549 in ZNF775, rs9658691 in FAS and rs11188249 in PDLIM1) were associated with ADHD in the whole sample (p < 0.05). Furthermore, 4 SNPs (rs1452898 in SLC4A4, rs13255144 in SAMD12, rs9658691 in FAS and rs11188249 in PDLIM1) showed associations with ADHD from maternal transmission (p < 0.001). Four SNPs showed paternal transmission p < 0.001 (rs7614907 in CDGAP, rs7790549 in ZNF775, and rs2644700 and rs604229 in NXN).

The Q-Q plot of parent-of-origin effects is presented in Appendix 1 (Fig. S1). As shown in Figure S1, the observed p values gradually depart from expected p values when −log10(p) > 3. The pattern suggests evidence for parent-of-origin effects.

Permutation results

Table 1 also shows that the empirical pointwise p values ranged from p = 0.00001 to p = 0.00043. Applying a permutation procedure for multiple test correction also yielded significant p values (corrected empirical p values), which ranged from p = 0.00053 to p = 0.013.

Fine-mapping

We examined all the SNPs within 19 genes in the IMAGE sample (2258 SNPs) and found an additional 33 SNPs within 9 genes that had parent-of-origin effects with nominal p < 0.05 (Table 2).

Table 2.

Thirty-three single nucleotide polymorphisms showing parent-of-origin effects with p < 0.05

Chr. SNP database Base pair position* Known gene GT AF All transmissions Maternal Paternal Parent-of-origin effect
T/NT χ2† p T/NT χ2 p T/NT χ2 p χ2‡ Z§ p
1 rs2799561 77542078 AK5 C/T 0.19 246/294 4.27 0.039 142/142 0.00 1.00 105/153 8.97 0.0028 4.72 2.17 0.030
1 rs2815324 77564277 AK5 C/T 0.20 251/301 4.53 0.033 144/146 0.01 0.91 108/156 8.76 0.0031 4.26 2.07 0.039
1 rs2815326 77571533 AK5 T/C 0.20 255/300 3.65 0.056 149/144 0.09 0.77 107/157 9.51 0.0020 5.96 2.44 0.015
1 rs2054017 77583700 AK5 G/A 0.06 101/84 1.56 0.21 39/49 1.14 0.29 62/35 7.52 0.0061 7.15 2.67 0.0079
1 rs9633478 77657870 AK5 A/G 0.08 109/118 0.37 0.55 43/64 4.16 0.041 67/55 1.19 0.28 4.96 2.23 0.026
1 rs1463502 232337970 SLC35F3 C/T 0.14 176/208 2.67 0.10 101/96 0.13 0.72 75/112 7.32 0.0068 4.81 2.19 0.029
1 rs12118979 232524008 SLC35F3 C/T 0.09 156/125 3.42 0.06 69/73 0.11 0.74 88/53 8.75 0.0031 5.47 2.34 0.019
2 rs12478741 154950445 GALNT13 T/A 0.07 92/106 0.99 0.32 52/43 0.85 0.36 40/63 5.14 0.023 5.02 2.23 0.025
2 rs1366750 155047405 GALNT13 A/G 0.15 192/218 1.65 0.20 107/97 0.49 0.49 86/122 6.26 0.012 5.10 2.05 0.04
2 rs1830018 155089021 GALNT13 G/T 0.19 259/278 0.67 0.41 139/122 0.98 0.32 121/155 4.44 0.035 4.76 2.26 0.024
2 rs11895478 155279369 GALNT13 T/C 0.30 353/326 1.07 0.30 168/182 0.64 0.42 186/143 5.36 0.02 4.95 2.18 0.029
2 rs3106653 155283806 GALNT13 G/T 0.30 363/329 1.67 0.20 174/183 0.28 0.60 190/145 5.78 0.016 4.41 2.10 0.036
4 rs2602049 72365934 SLC4A4 A/C 0.18 222/225 0.02 0.89 93/125 4.70 0.030 129/100 3.67 0.055 8.35 2.88 0.004
4 rs6854303 72501617 SLC4A4 G/A 0.24 289/311 0.81 0.37 134/174 5.20 0.023 155/137 1.11 0.29 5.51 2.34 0.019
4 rs4626166 72513226 SLC4A4 A/C 0.16 206/241 2.74 0.10 91/134 8.25 0.0041 116/108 0.29 0.59 5.81 2.41 0.016
4 rs4130912 72541637 SLC4A4 T/C 0.15 201/215 0.47 0.49 84/119 6.03 0.014 117/96 2.07 0.15 7.64 2.76 0.0059
4 rs4484264 72564200 SLC4A4 A/G 0.15 186/219 2.69 0.10 78/121 9.29 0.0023 108/98 0.49 0.49 7.13 2.66 0.0077
4 rs9997927 72576964 SLC4A4 C/A 0.29 321/358 2.02 0.16 149/196 6.42 0.011 173/163 0.30 0.58 4.70 2.17 0.030
4 rs10009080 72578718 SLC4A4 T/C 0.19 226/288 7.48 0.0062 100/165 16.0 0.000063 127/124 0.04 0.85 8.65 2.94 0.0033
4 rs4469035 72579342 SLC4A4 T/C 0.19 224/264 3.28 0.07 100/150 10.0 0.0015 125/115 0.42 0.52 7.20 2.68 0.0073
4 rs17484427 115089316 SLC4A4 G/C 0.15 216/211 0.06 0.81 90/123 5.11 0.024 126/88 6.75 0.0094 11.8 3.42 0.00063
6 rs149392 32997949 HLA-DOA C/T 0.07 112/121 0.35 0.56 41/62 4.28 0.039 71/59 1.11 0.29 5.05 2.34 0.025
6 rs1044429 33080620 HLA-DOA T/C 0.15 223/195 1.88 0.17 103/115 0.66 0.42 121/81 7.96 0.0047 6.74 2.60 0.0094
8 rs16928749 63436497 NKAIN3 T/C 0.09 130/131 0.01 0.96 76/53 4.13 0.042 55/79 4.33 0.037 8.40 2.89 0.0038
8 rs2351667 63440763 NKAIN3 G/A 0.14 191/178 0.46 0.95 112/76 6.93 0.0085 80/103 2.91 0.088 9.34 3.05 0.0023
8 rs16928789 63449820 NKAIN3 G/A 0.12 165/166 0.01 0.50 97/71 4.05 0.044 69/96 4.45 0.035 8.44 2.90 0.0037
8 rs1993126 63558534 NKAIN3 A/G 0.13 182/167 0.64 0.87 108/78 4.87 0.027 75/90 1.37 0.24 5.57 2.36 0.018
10 rs9658786 90766329 FAS T/C 0.14 189/205 0.65 0.42 83/118 6.10 0.014 106/87 1.87 0.17 7.33 2.70 0.007
10 rs11188256 97027568 PDLIM1 C/T 0.22 306/238 8.50 0.0036 165/104 13.9 0.00019 142/135 0.18 0.67 5.63 2.37 0.018
15 rs12913412 69549033 THSD4 C/G 0.19 243/260 0.57 0.45 136/120 1.00 0.32 107/140 4.41 0.036 4.84 2.20 0.028
15 rs11635579 69577402 THSD4 A/C 0.47 400/443 2.19 0.14 184/236 6.69 0.0097 217/206 0.24 0.63 4.74 2.18 0.030
15 rs12912888 69643738 THSD4 G/A 0.14 220/188 2.51 0.11 122/83 7.46 0.0063 99/106 0.24 0.62 5.19 2.28 0.023
15 rs8026019 69644931 THSD4 T/A 0.11 191/145 6.30 0.012 99/59 10.2 0.0014 93/87 0.20 0.65 4.14 2.04 0.042
Open in a new tab

AF = minor allele frequency of the SNP in founders; Chr. = chromosome; GT = genotype for the SNP; SNP = single nucleotide polymorphism; T/NT = transmitted/nontransmitted allele.

*

Physical position is based on NCBI Genome Build 36.3.

†

χ2 transmission disequilibrium test statistic.

‡

χ2 based on a 2 × 2 contingency test to evaluate the difference in transmission frequency between paternal and maternal haplotypes.

§

Z score for difference in paternal versus maternal odds ratios.

Nominal p value, asymptotic for parent-of-origin test.

Two genes, FAS and PDLIM1, which have been previously associated with psychiatric disorders, showed moderate parent-of-origin effects (p = 0.00086 for rs9658691 and p = 0.00077 for rs11188249) and strong maternal transmission (p = 0.000059 for rs9658691 and p = 0.0000068 for rs11188249). Therefore, we chose SNPs within FAS and PDLIM1 genes from the IMAGE sample for fine mapping. Part of the haplotype analysis results is presented in Table 3. The haplotype C-A based on rs9658691 and rs1926194 (D′ = 0.91) demonstrated a significant parent-of-origin effect with p = 0.000157, whereas for PDLIM1, the haplotype T-G based on rs17525659 and rs11188249 (D′ = 1.00) revealed a parent-of-origin effect with p = 0.000759. The associations of 8 SNPs within FAS and PDLIM1 are presented in Appendix 1 (Table S2).

Table 3.

Haplotype analyses for FAS and PDLIM1 genes

Gene Haplotype All transmissions Maternal Paternal Parent-of-origin effect
T/NT χ2* p† T/NT χ2 p T/NT χ2 p χ2‡ p
FAS rs9658691 rs1926194 7.31 0.063 16.07 0.0011 8.61 0.035
C A 100/125 2.54 0.11 39/81 15.00 0.00011 61/44 2.77 0.096 14.86 0.000157
T A 316/312 0.02 0.88 176/150 2.08 0.15 140/162 1.60 0.21 3.65 0.066
T G 300/270 1.18 0.28 158/139 1.22 0.27 142/131 0.44 0.51 0.08 0.80
PDLIM1 rs17525659 rs11188249 9.00 0.029 23.64 0.000029 0.42 0.94
G A 155/129 2.17 0.14 80/55 4.66 0.031 75/74 0.007 0.93 2.28 0.15
T A 261/239 0.88 0.35 130/103 3.14 0.077 131/136 0.094 0.76 2.26 0.15
T G 110/158 7.63 0.0057 39/90 20.7 0.0000053 71/68 0.065 0.80 12.00 0.000759
rs11188249 rs2296961 13.11 0.0044 22.41 0.000054 3.63 0.30
A C 246/288 2.46 0.12 127/143 0.95 0.33 119/145 2.57 0.11 0.21 0.66
A T 368/282 9.17 0.0025 186/126 11.60 0.00066 182/156 2.00 0.16 2.20 0.15
G T 99/133 4.53 0.033 37/74 12.57 0.00039 62/59 0.07 0.79 7.59 0.0078
rs17453855 rs11188256 12.47 0.0059 20.37 0.00014 1.45 0.69
A T 99/96 0.043 0.84 48/52 0.16 0.69 51/44 0.52 0.47 0.63 0.47
G C 260/184 10.85 0.00099 142/77 19.59 0.0000096 118/107 0.54 0.46 7.03 0.0093
G T 252/328 8.63 0.0033 116/175 12.05 0.00052 136/153 1.00 0.32 3.06 0.094
Open in a new tab

AF = minor allele frequency of the SNP in founders; Chr. = chromosome; GT = genotype for the SNP; SNP = single nucleotide polymorphism; T/NT = transmitted/nontransmitted allele.

*

χ2 transmission disequilibrium test statistic.

†

The globe p value for 2-SNP haplotype analysis based on a χ23 test or the p value for a single haplotype based on a χ21 test using UNPHASED.

‡

χ2 based on a 2 × 2 contingency test to evaluate the difference in transmission frequency between paternal and maternal haplotypes.

A 2-sided Fisher exact p value in SAS version 9.2 based on a 2×2 contingency (χ2) test to evaluate the difference in transmission frequency between paternal and maternal haplotypes.

Discussion

We tested parent-of-origin effects using a genome-wide design of IMAGE data with 600K SNPs. Forty-four SNPs, of which 22 were within 19 genes, were identified to have suggestive parent-of-origin effects at a nominal allelic p < 0.001. In particular, haplotype analyses for 2 genes, FAS and PDLIM1, further supported the parent-of-origin effects in those genes.

Interestingly, HLA-DOA at position 6p21.3 showed parent-of-origin effects. The HLA-DOA gene belongs to the HLA class II α chain paralogues. It has been reported that HLA showed strong paternal transmission in celiac disease25 and autism.26 Furthermore, HLA-DQB1, DQA1 and DRB1 are 230kb, 252kb and 306kb, respectively, away from HLA-DOA. Owing to the very strong linkage disequilibrium within the HLA region,27 the parent-of-origin effects in HLA-DOA may result from the linkage disequilibrium with flanking genes.

More interestingly, several genes, including FAS and PDLIM1, have been reported to be related to psychiatric disorders. For example, the FAS antigen (CD95) is a cell surface receptor that mediates cell apoptosis signalling, and recent investigations have shown that FAS-regulated apoptosis is linked to neurodegenerative lesions in the brains of patients with Alzheimer disease. One polymorphism of the FAS promoter region was associated with the risk of Alzheimer disease developing.28 The FAS gene, which plays a role in apoptosis, may be associated with Alzheimer disease by modulating the apoptosis and neuronal loss secondary to Alzheimer disease neuropathology.29 However, no significant differences in allelic and genotypic distributions were found between cases and controls, or patients with late- and early-onset Alzheimer disease, thus suggesting that these polymorphisms did not represent a risk factor for Alzheimer disease in the Italian population.30 Furthermore, PDLIM1 at position 10q22 might play a role in Alzheimer disease,31,32 serving as a scaffold to form a multi-protein complex that regulates actin cytoskeleton dynamics and playing a role in controlling neurite outgrowth.33 It has been reported that TAAR6 was associated with both schizophrenia and bipolar disorder in a Korean study34 and with schizophrenia in an Irish study,35 although the results need to be confirmed.

Several genes have been reported to be associated with other diseases. For example, CDGAP properties are well conserved between human and mouse species, and CDGAP may play an unexpected role in apoptosis and has suggestive association with coronary artery disease.36,37 In the present study, SLC4A4 at position 4q21 showed maternal transmissions, and this gene encodes a sodium bicarbonate cotransporter involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with cystic fibrosis.38 The SNP rs7790549 within ZNF775 at position 7q36.1 showed strong paternal transmission; however, the function of this gene is still unclear. In addition, other genes, such as AK5 and KAIN3 at position 8q12.3, have not been associated with any disease. The roles of these genes in ADHD need further study.

To compare our findings with those from previous studies of parent-of-origin effects, we examined the SNPs for the following 12 genes in the IMAGE sample: BDNF, DAT1 (SLC6A3), DDC, GNAL, HTR1B, SLC6A4, SNAP25, TPH2, DRD4, DRD5, FADS2 and ADRBK2. These genes have been reported to have paternal or maternal transmission or parent-of-origin effects in ADHD in previous studies.6–15 In the cleaned SNP data, we did not find any SNPs in the DRD4 gene. Furthermore, we could not confirm the paternal or maternal transmission or parent-of-origin effects (p < 0.01) for HTR1B, SLC6A4, DRD4, DRD5 and FADS2. However, we confirmed 14 SNPs within 7 genes (BDNF, DAT/DAT1/SLC6A3, DDC, GNAL, SNAP25, TPH2 and ADRBK2) showing paternal or maternal transmission or parent-of-origin effects with p < 0.01 (Table S3 in Appendix 1). Of these genes, our findings for TPH2 and ADRBK2 are consistent with those of Anney and colleagues10 using the IMAGE data. Consistent with the results of Mill and colleagues,14 we found nominal significance for paternal transmissions for the SNPs rs3787303 and rs3787283 in SNAP25. We also found similar maternal transmission in GNAL (p = 0.0081 for rs1477941, p = 0.002 for rs10468679 and p = 0.0003 for rs8087897) to those reported by Laurin and colleagues.11 Furthermore, Table S3 in Appendix 1 confirms the paternal transmission (p = 0.0019 for rs12288512) in BDNF found by Kent and colleagues.7 In addition, we confirmed the paternal transmission (p = 0.022 for rs3863145) for DAT1 reported by Hawi and colleagues.6,8

Based on QUANTO software,39 we had greater than 80% power at α = 5% to detect maternal and paternal transmission for a sample size of 846 (trios), relative risk of 1.3, population risk of 0.1 and allele frequency of 20%.

The mechanism of parent-of-origin effects is still unclear. One potential mechanism is “genomic imprinting” owing to epigenetic modification of the genome. For example, it has been shown that there is evidence to suggest that nearly 80 human genes show monoallelic expression consistent with imprinting,40 whereas the mechanism underlying the reading of the imprint can involve many aspects of gene expression, and the silencing can be stable throughout the individual’s life.41 Previous linkage and expression data showed that there are maternal-expressed imprinted genes at position 10q22, where PDLIM1 is located.42 However, imprinting is only one mechanism, and the utero maternal environment may influence parent-of-origin effect.43 It has been reported that the DDC gene may be imprinted in ADHD.9,10 However, the results need to be further confirmed.

This study has several strengths. First, we performed GWA analyses to identify genetic variants with parent-of-origin effects in ADHD. Based on our results, genes with strong parent-of-origin effects may not have large main effects in the whole sample. Second, we used a large sample with 846 trios from the IMAGE project. Furthermore, we used a Max (T) permutation procedure implemented using PLINK to correct multiple testing. The corrected p values ranged from p = 0.00053 to p = 0.013 (Table 1). Finally, we performed haplotype analyses for 2 genes (FAS and PDLIM1), and the haplotype analysis results further supported parent-of-origin effects in both genes.

Limitations

One limitation is that we had only 1 sample available for analysis. Furthermore, instead of reaching significant genome-wide association significance (p < 0.0000005), our study only reached suggestive associations with parent-of-origin effect (p < 0.001). Therefore, the findings in this study need to be further confirmed using other samples.

Conclusion

We have identified several interesting genes or regions with parent-of-origin effects using GWA analysis of a large sample from the IMAGE project. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in ADHD. Further work to identify additional variants and the disease-causing polymorphisms in the loci, and to examine the functions of these polymorphisms, will help us to better understand the pathogenesis of ADHD.

Acknowledgements

The dataset was obtained from the GAIN Database found at www.ncbi.nlm.nih.gov/projects/gap/ through the db-GAP accession number phs000016.v2.p2. The International Multi-Center ADHD Genetics Project (IMAGE) is a multisite, international effort supported by NIH grants R01MH081803 and R01MH62873 to Stephen V. Faraone. The genotyping of samples was provided through the Genetic Association Information Network (GAIN). Samples and associated phenotype data for the IMAGE project were provided by Dr. Faraone. We thank all the families who participated in this research.

Footnotes

Competing interests: None declared.

Contributors: K.-S. Wang acquired the data and designed the study. All authors contributed to the data analysis and interpretation. X. Liu and Q. Zhang offered critical guidance on the statistical analysis and contributed their statistical expertise. N. Aragam and Y. Pan performed the literature search. K.-S. Wang wrote the article, which all authors critically reviewed and approved for publication.

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