Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model.
Suicide is the second leading cause of death among adolescents in the USA, and rates are rising. Methods to identify individuals at risk are essential for implementing prevention strategies, and the development of a biomarker can potentially improve prediction of suicidal behaviors. Prediction of our previously reportedSKA2biomarker for suicide and PTSD is substantially improved by questionnaires assessing perceived stress or anxiety and is therefore reliant on psychological assessment. However, such stress-related states may also leave a biosignature that could equally improve suicide prediction. In genome-wide DNA methylation data, we observed significant overlap between waking cortisol-associated and suicide-associated DNA methylation in blood and the brain, respectively.



Using a custom bioinformatic brain to blood discovery algorithm, we derived a DNA methylation biosignature that interacts withSKA2methylation to improve the prediction of suicidal ideation in our existing suicide prediction model across both blood and saliva data sets. This biosignature was independently validated in the Grady Trauma Project cohort and interacted with HPA axis metrics in the same cohort. The biosignature showed a relationship with immune status by its correlation with myeloid-derived cell proportions in all data sets and with IL-6 measures in a prospective postpartum depression cohort. Three probes showed significant correlations with the biosignature: cg08469255 (DDR1), cg22029879 (ARHGEF10), and cg24437859 (SHP1), of whichSHP1methylation correlated with immune measures.



We conclude that this biosignature interacts withSKA2methylation to improve suicide prediction and may represent a biological state of immune and HPA axis modulation that mediates suicidal behavior.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
Makena L
ML
Clive
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
Marco P
MP
Boks
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
Christiaan H
CH
Vinkers
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
Lauren M
LM
Osborne
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
Jennifer L
JL
Payne
Department of Psychiatry, McLean Hospital, Harvard Medical School, Boston, MA 02478 USA ; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322 USA ; Howard Hughes Medical Institute, Chevy Chase, MD USA.
Kerry J
KJ
Ressler
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322 USA.
Alicia K
AK
Smith
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA ; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21218 USA.
Holly C
HC
Wilcox
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA ; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21218 USA ; The Mood Disorder Center, Johns Hopkins University, 720 Rutland Avenue, Ross Research Building 1070, Baltimore, MD 21205 USA.
Zachary
Z
Kaminsky
D000293:Adolescent; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D000070819:Discoidin Domain Receptor 1 / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D055106:Genome-Wide Association Study; D006306:Health Surveys; D006801:Humans; D008297:Male; D008960:Models, Psychological; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics; D018570:Risk Assessment; D013313:Stress Disorders, Post-Traumatic / Q000523:psychology*; D059020:Suicidal Ideation; D013405:Suicide / Q000523:psychology* / Q000706:statistics & numerical data
C577232:ARHGEF10 protein, human; D002868:Chromosomal Proteins, Non-Histone; D005819:Genetic Markers; D064067:Rho Guanine Nucleotide Exchange Factors; C516428:SKA2 protein, human; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
Biomarker; Childhood trauma; DNA methylation; Epigenetics; HPA axis; Illumina HM450 microarray; SKA2; Suicide