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. 2015 Sep;168(6):423-432.
doi: 10.1002/ajmg.b.32339. Epub 2015 Jul 14.

Epistatic and Gene Wide Effects in YWHA and Aromatic Amino Hydroxylase Genes Across ADHD and Other Common Neuropsychiatric Disorders: Association With YWHAE

Free PMC article

Epistatic and Gene Wide Effects in YWHA and Aromatic Amino Hydroxylase Genes Across ADHD and Other Common Neuropsychiatric Disorders: Association With YWHAE

Kaya K Jacobsen et al. Am J Med Genet B Neuropsychiatr Genet. .
Free PMC article


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 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Keywords: ADHD; SCZ; TH; TPH; YWHA.


Figure 1
Figure 1
14‐3‐3 proteins in the regulation of monoamine biosynthesis. (A) shows a literature based illustration of the presynaptic biosynthesis of dopamine (DA) and noradrenaline (NA) from tyrosine (Tyr) via dihydroxyphenylalanine (L‐Dopa), involving the enzymes tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC/DDC), dopamine β‐hydroxylase (DBH), and the vesicular monoamine transporter (VMAT2/SLC18A2). Black arrows illustrate chemical transformations or transport processes, whereas red double arrows illustrate protein–protein interactions. Biosynthesis of serotonin (SE) from tryptophan (Trp) via 5‐hydroxytryptophan (5HTrp) by tryptophan hydroxylase 1 or 2 (TPH1 or TPH2) and AADC with subsequent transport into storage vesicles is also shown. Reuptake of released DA, NA, or SE by dopamine transporter (DAT1/SLC6A3), noradrenaline transporter (NET/SLC6A2), or serotonin transporter (SERT/SLC6A4) is also shown. Phosphorylated TH, TPH1, and TPH2 may interact with members of the mammalian 14‐3‐3 protein family (YWHA proteins), which may modulate the enzymatic activities, stability, or cellular localization [McKinney et al., 2005; Kleppe et al., 2014]. A reported interaction between SLC6A3 and YWHAZ is also depicted [Ramshaw et al., 2013]. (B) illustrates the formation of possible dimers within the mammalian 14‐3‐3 protein family. The reported interactions are shown between different monomers by formation of heterodimers (14‐3‐3ϵ/YWHAE with 14‐3‐3β/YWHAB, 14‐3‐3γ/YWHAG, 14‐3‐3η/YWHAH, 14‐3‐3ζ/YWHAZ, and 14‐3‐3τ/YWHAQ) and by formation of homodimers [Yang et al., 2006]. 14‐3‐3σ/YWHAS is found to preferentially form homodimers, whereas YWHAE is found as heterodimers in cells. Panel (C) shows the activation of bovine TH, phosphorylated on Ser19 by p38‐regulated/activated protein kinase, in the presence of different 14‐3‐3 isoforms reported in midbrain [Wang et al., 2009]. The experiments were performed essentially as described [Toska et al., 2002, Ghorbani et al. in preparation). Different activation potency between the YWHAs suggests a variable risk for association with monoamine related disorders between the YWHA‐genes.
Figure 2
Figure 2
Likelihood ratio tests of all interactions examined in this study. Each small square represents the P‐value of a single test. As indicated by the gradient color of green, the darker shades represent smaller, more significant P‐values. SNPs are grouped along the axes by genes, listed alphabetically and separated by grid lines. Along the diagonal, as indicated by a line, are the P‐values of the single SNP tests. The lower right triangle represents additive tests, which were not the focus of this study. The upper left triangle represents interaction tests between a pair of SNPs. Two dark green squares correspond to the SNP interactions represented in Table I. The numerical values of each test are presented in Supplementary Table S2.

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