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Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

Background Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. Objective The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Methods Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. Results We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. Conclusions The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

Background Suicidal behavior may be divided into completed suicide, suicide attempts, and suicidal ideation. It has been suggested that these behaviors represent a continuum and result from the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. Methods The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide) and 419 non-suicide controls. Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. Methylation profile from individuals in the target sample was assessed with the Illumina Infinium Human Methylation EPIC BeadChip. Results We identified 153 differentially methylated sites between individuals with low and high-PRS. From these, 91 sites were hypermethylated and 62 hypomethylated in the high PRS group relative to low PRS group. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment and ATP binding. Discussion To our knowledge, this is the first study integrating polygenic risk scores and DNA methylation in suicidality. Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

We analyzed 307 Mexican-Mestizo (admixed) males from Mexico City with the Powerplex® Y23 system. The complete list of Y-STR haplotypes was uploaded into the YHRD database (accession number YA004275). The discriminatory capacity (98.70 %) and gene diversity (D = 99.99 %) were calculated, improving the haplotype diversity regarding previous studies in Mexico based on 17 Y-STRs and 12 Y-STRs. Haplogroup distribution assignment was inferred by means of two different online-available algorithms. The Native American Q* haplogroup was the most frequent (66.2 %), followed by the European R1b lineage (19.5 %). In addition, eight Eurasian (3.9%) and two African (6.6%) haplogroups were observed in this population sample from Mexico City. Interestingly, AMOVA test showed a low but significant differentiation among Mexican-Mestizos (Fst = 1.52%; p = 0.0000), suggesting that four population clusters allow to explain their genetic structure according to geographic criteria: north, west, center, and south.

The maternal ancestry (mtDNA) has important applications in different research fields, such as evolution, epidemiology, identification, and human population history. This is particularly interesting in Mestizos, which constitute the main population in Mexico (∼93%) resulting from post-Columbian admixture between Spaniards, Amerindians, and African slaves, principally. Consequently, we conducted minisequencing analysis (SNaPshot) of 11 mitochondrial single-nucleotide polymorphisms in 742 Mestizos of 10 populations from different regions in Mexico. The predominant maternal ancestry was Native American (92.9%), including Haplogroups A, B, C, and D (47, 23.7, 15.9, and 6.2%, respectively). Conversely, European and African ancestries were less frequent (5.3 and 1.9%, respectively). The main characteristics of the maternal lineages observed in Mexican-Mestizos comprised the following: 1) contrasting geographic gradient of Haplogroups A and C; 2) increase of European lineages toward the Northwest; 3) low or absent, but homogeneous, African ancestry throughout the Mexican territory; 4) maternal lineages in Mestizos roughly represent the genetic makeup of the surrounding Amerindian groups, particularly toward the Southeast, but not in the North and West; 5) continuity over time of the geographic distribution of Amerindian lineages in Mayas; and 6) low but significant maternal population structure (FST = 2.8%; P = 0.0000). The average ancestry obtained from uniparental systems (mtDNA and Y-chromosome) in Mexican-Mestizos was correlated with previous ancestry estimates based on autosomal systems (genome-wide single-nucleotide polymorphisms and short tandem repeats). Finally, the comparison of paternal and maternal lineages provided additional information concerning the gender bias admixture, mating patterns, and population structure in Mestizos throughout the Mexican territory.