A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder

Gaynor, Sophia C.; Breen, Marie E.; Monson, Eric; Klerk, Kelly de; Parsons, Meredith G.; DeLuca, Adam P.; Scheetz, Todd E.; Zandi, Peter P.; Potash, James B.; Willour, Virginia L.

doi:10.1002/ajmg.b.32479

Cited by 15 publications

(10 citation statements)

References 61 publications

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“…Raw data were processed following standard protocols used in earlier reports (Gaynor et al, 2016). In short, raw image files were first converted to the FASTQ format and the reads were aligned to the human reference genome (hg19, GRCh37).…”

Section: Methodsmentioning

confidence: 99%

Genetic Association of Olanzapine Treatment Response in Han Chinese Schizophrenia Patients

Zhou

et al. 2019

Front. Pharmacol.

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Olanzapine, a second-generation antipsychotic medication, plays a critical role in current treatment of schizophrenia (SCZ). It has been observed that the olanzapine responses in schizophrenia treatment are different across individuals. However, prediction of this individual-specific olanzapine response requires in-depth knowledge of biomarkers of drug response. Here, we performed an integrative investigation on 238 Han Chinese SCZ patients to identify predictive biomarkers that were associated with the efficacy of olanzapine treatment. This study applied HaloPlex technology to sequence 143 genes from 79 Han Chinese SCZ patients. Our result suggested that there were 12 single nucleotide polymorphisms (SNPs) had significant association with olanzapine response in Han Chinese SCZ patients. Using MassARRAY platform, we tested that if these 12 SNPs were also statistically significant in 159 other SCZ patients (independent cohort) and the combined 238 SCZ patients (composed of two tested cohorts). The result of this analysis showed that 2 SNPs were significantly associated with the olanzapine response in both independent cohorts (rs324026, P = 0.023; rs12610827, P = 0.043) and combined SCZ patient population (rs324026, adjust P = 0.014; rs12610827, adjust P = 0.012). Our study provides systematic analyses of genetic variants associated with olanzapine responses of Han Chinese SCZ patients. The discovery of these novel biomarkers of olanzapine-response will facilitate to advance future olanzapine treatment specific for Han Chinese SCZ patients.

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Section: Methodsmentioning

confidence: 99%

Genetic Association of Olanzapine Treatment Response in Han Chinese Schizophrenia Patients

Zhou

et al. 2019

Front. Pharmacol.

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“…Individual‐variant tests were performed using Firth's penalized logistic regression method (Firth, ) in the “logistf” R package (v1.21; Heinze & Puhr, ), including sex and the first three principal components from our attempted suicide GWAS as covariates. Age was not included as a covariate in this study as there was no significant difference ( p ‐value = .75; Table S1; Gaynor et al, ; Willour et al, ). Individual variants were analyzed in the overall sample set and in sex‐specific subsets (male‐only, female‐only).…”

Section: Methodsmentioning

confidence: 99%

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

Reichman

Gaynor

Monson

et al. 2019

American J of Med Genetics Pt B

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Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones.The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female-and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide. K E Y W O R D Sglutamatergic signaling, haplotype, LRRTM4, sex specificity, suicidal behavior

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“…We used a customized SureSelect Target Enrichment System (Agilent Technologies, Santa Clara, CA, U.S.A.) to capture and sequence our chosen targets (as previously described in [36]). Briefly, 3 μg genomic DNA was sheared, prepared into a library using adaptors and hybridized to biotinylated RNA baits.…”

Section: Methodsmentioning

confidence: 99%

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Breen¹,

Gaynor²,

Monson³

et al. 2016

PLoS ONE

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FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene-level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10−4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene-level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior.

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A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder

Cited by 15 publications

References 61 publications

Genetic Association of Olanzapine Treatment Response in Han Chinese Schizophrenia Patients

Genetic Association of Olanzapine Treatment Response in Han Chinese Schizophrenia Patients

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

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