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Review
. 2019 Jun;20(9):669-684.
doi: 10.2217/pgs-2019-0015.

The ANKS1B gene and its associated phenotypes: focus on CNS drug response

Rabha M Younis  1 , Rachel M Taylor  2 , Patrick M Beardsley  3   4 , Joseph L McClay  1
Affiliations
Review

The ANKS1B gene and its associated phenotypes: focus on CNS drug response

Rabha M Younis et al. Pharmacogenomics. 2019 Jun.

Abstract

The ANKS1B gene was a top finding in genome-wide association studies (GWAS) of antipsychotic drug response. Subsequent GWAS findings for ANKS1B include cognitive ability, educational attainment, body mass index, response to corticosteroids and drug dependence. We review current human association evidence for ANKS1B, in addition to functional studies that include two published mouse knockouts. The several GWAS findings in humans indicate that phenotypically relevant variation is segregating at the ANKS1B locus. ANKS1B shows strong plausibility for involvement in CNS drug response because it encodes a postsynaptic effector protein that mediates long-term changes to neuronal biology. Forthcoming data from large biobanks should further delineate the role of ANKS1B in CNS drug response.

Keywords: BMI; NMDA; antipsychotics; cognition; corticosteroids; drugs of abuse; glutamatergic neurotransmission; postsynaptic density; serotonin; synapse to nucleus communication; synaptic plasticity.

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Conflict of interest statement

Financial & competing interests disclosure

RM Younis was funded through a graduate studentship from Virginia Commonwealth University (VCU) School of Pharmacy and this review was completed in partial fulfillment of the doctoral requirements in Pharmaceutical Sciences at VCU. This work was funded through a pilot award from the Endowment Fund of the Wright Center for Clinical and Translational Research at VCU and UL1TR000058 from the National Center for Advancing Translational Sciences. JL McClay was partially supported by National Institute of Mental Health grant R56MH107879. PM Beardsley was supported by NIDA N01DA-14-8917, NIDA N01DA-17-8932 and DOJ D-17-OD-0092. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Linear protein domain structure of the full length ANKS1B protein.
The ANKS1B acronym comes from ‘ANKyrin repeat and Sterile alpha motif domain containing 1B’. The Ankyrin repeats (ANK, green boxes) link membrane proteins to the underlying cytoskeleton; the second SAM (pink triangles) domain contains a nuclear import signal; the PTB (pink rectangle) domain is involved in tyrosine kinase signaling. Light pink areas on the main axis represent regions of low complexity. ANKS1B is now known to be a protein of the postsynaptic density that translocates to the cell nucleus to regulate neuronal biology. Domain structure adapted from the SMART database (http://smart.embl-heidelberg.de/) [5]. ANK: Ankyrin; PTB: Phosphotyrosine binding; SAM: Sterile alpha motif.
Figure 2.
Figure 2.. Diagram showing ANKS1B protein translocation from the postsynaptic density to the nucleus.
ANKS1B protein has been found in complexes with several PSD components, including PSD-95 and glutamate receptors of both ionotropic (NMDA) and metabotropic (mGluR) types. ANKS1B protein has also been shown to be a direct interacting partner of the serotonin 2A (5HT2A) receptor, which is a major target for second-generation antipsychotic drugs. The figure shows how, upon stimulation of NMDA receptors, ANKS1B dissociates from the PSD and migrates to the cell nucleus where it affects neuronal regulation, including protein expression. To date, it remains to be determined if 5HT2A or metabotropic glutamate receptor stimulation results in the same outcome.
Figure 3.
Figure 3.. Graph of ANKS1B genome-wide association studies findings, plotted by position in the gene (x-axis).
The approximate exon–intron structure is also shown below the x-axis. Each GWAS finding is labeled with the associated phenotype (see Table 1 for more details). For each genome-wide association study finding, the -log10 (p-value) of the top SNP is plotted on the y-axis, with more significant findings exhibiting larger y-axis values. Points labeled ‘Cytokine/GF’ refer to associations with circulating cytokines and growth factors as reported by [31]. ACE: Angiotensin-converting enzyme; ALS: Amyotrophic lateral sclerosis; AP: Antipsychotic; SCZ: Schizophrenia.
Figure 4.
Figure 4.. Network of known ANKS1B direct protein interactions.
The network graph was generated from public data on direct protein–protein interactions only using InBioMap™ from Intomics (www.intomics.com).
See this image and copyright information in PMC

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