ADHDgene Database

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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Study Report

Basic Info

Reference	Domene S, 201121184580
Citation	Domene S., Stanescu H., Wallis D., Tinloy B., Pineda D. E., Kleta R., Arcos-Burgos M., Roessler E. and Muenke M. (2011) "Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility." Am J Med Genet B Neuropsychiatr Genet, 156B(1): 11-8.
Study Design	case-control
Study Type	Mutational study
Sample Size	139 cases, 52 controls
Predominant Ethnicity

Detail Info

Summary	In this study, they identified LPHN3, a novel ADHD susceptibility gene harbored in 4q, and showed that a LPHN3 common haplotype confers susceptibility to ADHD and predicts effectiveness of stimulant medication. They presented the mutational analysis of the entire coding region of LPHN3 in a cohort of 139 ADHD subjects and 52 controls from across the USA. They identified 21 variants, of which 14 have been reported and 7 are novel. These include 5 missense, 8 synonymous, and 8 intronic changes. Interestingly, neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations, suggesting that non-coding variations determining the quantity and/or quality of LPHN3 isoforms are the likely contributors to this common behavioral disorder.
Total Sample	A total of 139 unrelated patients diagnosed with ADHD and 52 commercially available normal controls not screened for ADHD were studied.
Diagnosis Description	based on DSMIVR criteria; see Palacio et al., 2004; Acosta et al., 2008; Arcos- Burgos et al., 2010
Technique	Genomic DNA was extracted from peripheral blood or transformed lymphoblast cell lines by standard methods. Mutation detection was performed by PCR-based denaturing high performance liquid chromatograhy (dHPLC) analysis followed by direct sequencing. PCR amplification, dHPLC analysis WAVE(TM) and WAVEMAKER(TM) (Transgenomic, Omaha, NE), amplicon purification Qiagen PCR purification kit (Qiagen, Valencia, CA), and DNA sequencing Big Dye(TM) version 3.1 terminator cycle sequencing on an ABI 3100 (Applied Biosystems, Foster City, CA) instrument were performed according to the manufacturers instructions, essentially as previously described [Schimmenti et al., 2003]. dHPLC has a sensitivity and specificity of over 96% [Xiao and Oefner, 2001]. For this study we used the reference sequence NT_022778.15 from NCBI to determine which exons to examine.
Analysis Method	They annotated LPHN3 using the UCSC Genome Browser custom track capabilities.They included information derived fromdatabases (such as expression information on mRNAs, ESTs, spliced ESTs from NCBI, UCSC, and EMBL; miRNA genes from AceView; miRNA binding sites from UCSC; variation information from dbSNP; domains and motifs from SwissPro, interPro, Pfam, and ProDom). They then placed the variants in their biological context within their annotation and analyzed if they fell in the following: predicted domains, motifs, glycosylation and/or phosphorylation sites, splice sites (donor, branch point, acceptor), splice site regulators (AG nucleotide Exclusion Zones: AGEZ; Exonic Splice-site Enhancers using ESEfinder 2.0) [Cartegni et al., 2003b], predicted 30UTR regulatory elements (including miRNAs, miRNA binding sites) and conserved short sequence-stretches: Exact Plus [Antonellis et al., 2006], Vista [Frazer et al., 2004]. Swissprot Q9HAR2 was used as the reference sequence for variant nomenclature. They performed signal peptide search using Signal P3.0 [Bendtsen et al., 2004], EUnited Kingdomaryotic Linear Motif (ELM) analysis [Puntervoll et al., 2003] and a Kyte-Doolittle/Hopp-Woods hydropathy plot-as implemented in the Molecular Toolkit/Protein Hydrophobicity Plots (www.vivo.colostate.edu/molkit).
Result Description	Twenty-four exons, including all intron-exon boundaries, were screened for heterozygous mutations in the USA population sample of ADHD patients and normal controls using dHPLC. In total, we detected 21 variants out of which 14 have been reported (dbSNP build 130) and 7 are novel. These include 5 missense, 8 synonymous, and 8 intronic changes. Interestingly, neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations, suggesting that non-coding variations determining the quantity and/or quality of LPHN3 isoforms are the likely contributors to this common behavioral disorder.

SNPs reported by this study (count: 14)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs10434219	c.612C>T		Obs_HET/Pred_HET=0.374/0.401	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs10013832	c.1977G>A		ND	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs12648576	c.1869+20G>A		ND	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs12509110	c.2782C>G		ND	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs1397548	c.2811A>G		Obs_HET/Pred_HET=0.466/0.456	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs1397547	c.2709G>C		Obs_HET/Pred_HET=0.177/0.168	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs2305339	c.1908-4G>A		Obs_HET/Pred_HET=0.462/0.429	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs2172802	c.269+51A>G		ND	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs34586911	c.180G>A		Obs_HET/Pred_HET=0.251/0.252	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs34246405	c.2322T>C		Obs_HET/Pred_HET=2/178	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs734644	c.2079T>C		Obs_HET/Pred_HET=0.459/0.427	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs56038622	c.3032-45A>T		Obs_HET/Pred_HET=0.006/0.008	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs9312082	c.1195+17G>A		Obs/Pred_HET=0.374/0.401	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend
rs73823293	c.3191+31G>A		Obs_HET/Pred_HET=0.308/0.314	neither susceptibility nor protective haplotype alleles are ...... neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations More...	Trend

Other variant reported by this study (count: 7)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
LPHN3 2348C>T	c.2348C>T		Obs_HET/Pred_HET=0.324/0.353 Obs_HET/Pred_HET=0.324/0.353	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend
LPHN3 3387+36A>G	c.3387+36A>G		Obs_HET/Pred_HET=1/167 Obs_HET/Pred_HET=1/167	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend
LPHN3 471G>A	c.471G>A		Obs_HET/Pred_HET=0.478/0.473 Obs_HET/Pred_HET=0.478/0.473	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend
LPHN3 1670G>A	c.1670G>A		ND ND	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend
LPHN3 839G>T	c.839G>T		ND ND	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend
LPHN3 1869-13T>C	c.1869-13T>C		Obs_HET/Pred_HET=176/176 Obs_HET/Pred_HET=176/176	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend
LPHN3 1394G>A	c.1394G>A		Obs_HET/Pred_HET=0.177/0.168 Obs_HET/Pred_HET=0.177/0.168	neither susceptibility nor protective haplotype alleles are associated with obviously significant coding region changes, or canonical splice site alterations	Trend

Genes reported by this study (count: 1)