Epistatic and gene wide effects in YWHA and aromatic amino hydroxylase genes across ADHD and other common neuropsychiatric disorders: Association with YWHAE

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

Gene expression dynamics following mithramycin treatment: A possible model for post‐chemotherapy cognitive impairment

“…These data suggest that complex I, the first complex of the OXPHOS, which contributes about 40% of the proton motive force that drives adenosine 5′‐triphosphate (ATP) synthesis by ATP synthase (complex V) and is a main site for ROS production, is a vulnerable module in situations requiring cellular adaptation. The expression of PSEN1, DAB1, YWHAE and JUN, all associated with synaptic plasticity and with cognitive function also showed inverse time‐dependent dynamics. Two additional genes showed similar inverse trajectory in MTR treated rats, PACS1 and AP2B1.…”

“…Out of the 30 qRT‐PCR validated genes, 3 showed a significant correlation between expression and behavioural responses. A significant negative correlation was observed between the percentage of errors in the T‐maze test and the expression levels of the following genes in the PFC: NDUFV2, which encodes for mitochondrial Complex I subunit ( R = −0.781, P < .01) (Figure A); Ywhae, encoding for 14‐3‐3 ε protein which is an adapter protein implicated in the regulation of a large spectrum of both general and specialized signalling pathways and has been implicated in schizophrenia and Alzheimer disease ( R = −0.703, P < .01) (Figure B); DAB1, which is involved in directing neuronal positioning in the developing brain ( R = −0.582, P < .05) (Figure C). In addition, a significant negative correlation was observed between the anxiety index and PFC NDUFV2 gene expression levels ( R = −0.580, P < .05) (Figure D).…”

“…YWHAE gene product belongs to the 14‐3‐3 family of proteins, which are involved in diverse vital cellular processes. This gene was found to be associated with common neuropsychiatric disorders such as ADHD, schizophrenia, bipolar disorder and Alzheimer's disease . Ywhae knockout mice show moderate defects in working memory and anxiety‐like behaviour .…”

Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease

“…Serotonin dysregulation has also been proposed to play a role in autism [99]. Variants in TPH2 have also been associated with major depression, bipolar disorder, suicidal behavior, personality disorder, and ADHD [100]. However, in large genome wide association studies, common variants in TH, TPH1, or TPH2 have not shown convincing associations with any known human phenotypes tested so far.…”

“…However, in large genome wide association studies, common variants in TH, TPH1, or TPH2 have not shown convincing associations with any known human phenotypes tested so far. A recent comprehensive analysis of variants in TH, TPH1, and TPH2, as well as the 14-3-3 genes (YWHAs), across several psychiatric disorders has shown modest effects for the hydroxylase genes, but significant association of 14-3-3 epsilon (YWHAE) with schizophrenia [100].…”