International Multicentre persistent AC (2012). The genetics of attention deficit/hyperactivity disorder in adults, a review

1] Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [2] Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Molecular Psychiatry (Impact Factor: 14.5). 11/2011; 17(10):960-87. DOI: 10.1038/mp.2011.138
Source: PubMed


The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.

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    • "In our gene-based and gene-complex evaluation, we have examined childhood ADHD only. However, slightly different genetic risk factors may be associated with the persistent and remitting forms of this disorder [Franke et al., 2011]. Similarly, epistasis has been tested in our Norwegian sample of adult ADHD only and its further exploration in childhood ADHD (as well as other neuropsychiatric disorders) is warranted. "
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    ABSTRACT: Monoamines critically modulate neurophysiological functions affected in several neuropsychiatric disorders. We therefore examined genes encoding key enzymes of catecholamine and serotonin biosynthesis (tyrosine and tryptophan hydroxylases-TH and TPH1/2) as well as their regulatory 14-3-3 proteins (encoded by YWHA-genes). Previous studies have focused mainly on the individual genes, but no analysis spanning this regulatory network has been reported. We explored interactions between these genes in Norwegian patients with adult attention deficit hyperactivity disorder (aADHD), followed by gene-complex association tests in four major neuropsychiatric conditions; childhood ADHD (cADHD), bipolar disorder, schizophrenia, and major depressive disorder. For interaction analyses, we evaluated 55 SNPs across these genes in a sample of 583 aADHD patients and 637 controls. For the gene-complex tests, we utilized the data from large-scale studies of The Psychiatric Genomics Consortium (PGC). The four major neuropsychiatric disorders were examined for association with each of the genes individually as well as in three complexes as follows: (1) TPH1 and YWHA-genes; (2) TH, TPH2 and YWHA-genes; and (3) all genes together. The results show suggestive epistasis between YWHAE and two other 14-3-3-genes - YWHAZ, YWHAQ - in aADHD (nominal P-value of 0.0005 and 0.0008, respectively). In PGC data, association between YWHAE and schizophrenia was noted (P = 1.00E-05), whereas the combination of TPH1 and YWHA-genes revealed signs of association in cADHD, schizophrenia, and bipolar disorder. In conclusion, polymorphisms in the YWHA-genes and their targets may exert a cumulative effect in ADHD and related neuropsychiatric conditions, warranting the need for further investigation of these gene-complexes. © 2015 Wiley Periodicals, Inc. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2015; 168(6). DOI:10.1002/ajmg.b.32339 · 3.42 Impact Factor
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    • "Neuropsychiatric Genetics suggest strong candidate genes for ADHD [Genro et al., 2010; Franke et al., 2012]. The most frequently reported and replicated associations with dopaminergic gene variants are for the genes encoding the D4 receptor (DRD4) and the dopamine transporter (DAT1 or SLC6A3). "
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    ABSTRACT: Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2015; 168(2). DOI:10.1002/ajmg.b.32283 · 3.42 Impact Factor
    • "ploPS , F ST and LSBL as a strong selection signal ( Table 2 ; Figure S3 ) . CDH13 encod - ing a GPI - anchored member of the cadherin superfamily , has been associated with atherosclerosis protection ( UCSC Genome Browser ; Lee et al . 2013 ; Takeuchi et al . 2007 ) and adiponectin levels ( Dastani et al . 2012 ) , neuropsychiat - ric disorders ( Franke et al . 2012 ) , and blood pressure ( Org et al . 2009 ) . A recent meta - GWAS carried out in the Afri - can populations revealed a significant association of this candidate gene with severe malaria ( Band et al . 2012 ; Man - gano and Modiano 2014 ) ."
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    ABSTRACT: The indigenous populations from Peninsular Malaysia, locally known as Orang Asli, continue to adopt an agro-subsistence nomadic lifestyle, residing primarily within natural jungle habitats. Leading a hunter-gatherer lifestyle in a tropical jungle environment, the Orang Asli are routinely exposed to malaria. Here we surveyed the genetic architecture of individuals from four Orang Asli tribes with high-density genotyping across more than 2.5 million polymorphisms. These tribes reside in different geographical locations in Peninsular Malaysia and belong to three main ethno-linguistic groups, where there is minimal interaction between the tribes. We first dissect the genetic diversity and admixture between the tribes and with neighboring urban populations. Later, by implementing five metrics, we investigated the genome-wide signatures for positive natural selection of these Orang Asli, respectively. Finally, we searched for evidence of genomic adaptation to the pressure of malaria infection. We observed that different evolutionary responses might have emerged in the different Orang Asli communities to mitigate malaria infection.
    Human Genetics 01/2015; 134(4). DOI:10.1007/s00439-014-1525-2 · 4.82 Impact Factor
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