Vanessa Gonçalves

• Centre for Addiction and Mental Health

The brain requires a large amount of energy, primarily obtained through glucose metabolism, which appears to be disrupted in various neuropsychiatric disorders. The etiology of neuropsychiatric disorders is complex and involves genetic factors that are slowly being identified. To investigate whether glucose metabolism-related genes are associated w...

Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder with clear evidence of genetic vulnerability, although specific risk factors are not fully understood. Mitochondrial dysfunction has been implicated in other severe neuropsychiatric disorders, particularly through its role in oxidative stress, and thus merits exploration in O...

The pace of biological aging varies between people independently of chronological age and mitochondria dysfunction is a key hallmark of biological aging. We hypothesized that higher functional impact (FI) score of mitochondrial DNA (mtDNA) variants might contribute to premature aging and tested the relationships between a novel FI score of mtDNA va...

Late-life depression (LLD) is often accompanied by medical comorbidities such as psychiatric disorders and cardiovascular diseases, posing challenges to antidepressant treatment. Recent studies highlighted significant associations between treatment-resistant depression (TRD) and polygenic risk score (PRS) for attention deficit hyperactivity disorde...

Background Mitochondrial dysfunction is implicated in the neuropathology of bipolar disorder (BD). Higher circulating cell-free mitochondrial DNA (ccf-mtDNA), generally reflecting poorer mitochondrial health, has been associated with greater symptoms severity in BD. The current study examines the association of serum ccf-mtDNA and brain structure i...

Background: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF)....

Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an i...

Background: Late-life depression (LLD) is a prevalent and disabling mental illness affecting 1% to 5% of the elderly population. The pathophysiology of LLD involves various biologi�cal processes, including pro-inflammatory cascades, mitochondrial dysfunction and increased oxidative stress (OS). The mitochondria are the primary source of ROS, being...

Background: Schizophrenia is a complex disorder with clinical and biological heterogeneity. Despite of the recent success in identifying contributing genetic variants from the nuclear genome, the effective diagnosis, treatment and prevention strategies are largely absent. Mitochondria are crucial for the brain physiology, and mitochondrial DNA (mtD...

Background: Mitochondria are the main energy source for neurons and other brain cells and play crucial roles in various neural processes, such as neurogenesis, neuroplasticity, and neurotransmission. The dysfunction in those organelles may alter critical neuronal processes underlying abnormal brain development and cognitive impairment in psychosis...

Background The bidirectional relationship between sleep disturbances and depression is well documented, yet the biology of sleep is not fully understood. Mitochondria have become of interest not only because of the connection between sleep and metabolism but also because of mitochondria's involvement in the production of reactive oxygen species, wh...

[This corrects the article DOI: 10.3389/fpsyt.2021.734077.].

Background: The prevalence of insomnia and hypersomnia in depressed individuals is substantially higher than that found in the general population. Unfortunately, these concurrent sleep problems can have profound effects on the disease course. Although the full biology of sleep remains to be elucidated, a recent genome-wide association (GWAS) of ins...

Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue me...

Background Oxidative stress (OS) has been implicated in the pathophysiology of late-life depression (LLD). Mitochondria are the primary source of oxidative stress and can be significantly damaged with increased OS. Circulating cell-free mtDNA (ccf-mtDNA) is a marker of cellular stress and mitochondria damage triggered by oxidative stress. Methods:...

Objectives/Methods: The biology underlying sleep is not yet fully elucidated, but it is known to be complex and largely influenced by circadian rhythms. Compelling evidence supports of a link among circadian rhythms, sleep and metabolism, which suggests a role for mitochondria. These organelles play a significant role in energy metabolism via oxida...

Background Obsessive-Compulsive Disorder (OCD) has a complex genetic component and may be preceded by environmental stressors. The spindle and kinetochore associated complex subunit 2 (SKA2) gene interacts with the glucocorticoid receptor and is implicated in mediating hypothalamic–pituitary-adrenal (HPA) axis function but has yet to be examined in...

Background Antipsychotics, especially most of the second-generation antipsychotics, have a high risk for metabolic syndrome and antipsychotic-induced weight gain (AIWG). A promoter variant of the leptin (LEP) gene, -2548G/A (rs7799039), has been associated with AIWG in several studies. The aim of this study was to evaluate this association in the C...

Cognitive impairment is highly prevalent in the progression of both diabetes mellitus and bipolar disorder. The relationship between insulin resistance in diabetes and the risk of developing major neurocognitive disorders such as Alzheimer's disease has been well described. Insulin resistance and the associated metabolic deficiencies lead to bioche...

Sleep disturbance affects about 75% of depressed individuals and is associated with poorer patient outcomes. The genetics in this field is an emerging area of research. Thus far, only core circadian genes have been examined in this context. We expanded on this by performing a genome-wide association study (GWAS) followed by a preplanned hypothesis-...

Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondri...

Background Antipsychotic drugs are the primary intervention in the treatment of psychotic disorders, however, the use of antipsychotics is often accompanied by weight gain and metabolic syndrome. A recent Genome-Wide Association Study (GWAS) investigating a Han Chinese sample suggested a possible role of rs1097714 and rs10977154 variants of the pro...

Background Mitochondria play a significant role in human diseases. Genetic variants in mitochondrial DNA (mtDNA) – and in nuclear genes coding for mitochondrial function - have been associated with disease. Mitochondrial disease is clinically characterised by complex metabolic, neurological, muscular and psychiatric symptoms. SNPs in mtDNA have bee...

Background Disturbed mitochondrial function has been implicated in psychiatric disease. All mitochondria contain a small maternally inherited DNA (mtDNA) of 16.6 kb. Through evolution and genetic drift, the mtDNA sequence has become fixed into haplogroups (hgs) with a characteristic population and geographical distribution. Different hgs exhibit va...

Background Schizophrenia (SCZ) is a severe psychiatric disorder wherein the genetic risk factors are far from being fully understood. Multiple lines of evidence have suggested mitochondrial dysfunction in SCZ, but association of mitochondrial variants with SCZ has not been extensively investigated. Methods We conducted gene-based and gene-set anal...

Background Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNPs. Associations of hgs with geographical origin, disease and physiological characteristics have been reported, but have frequently not been reproducible. We assessed, using 418 mtDNA SNPs on the PsychChip (Illumina), the spatio-temporal distribution...

Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spati...

PCAs of mtDNA SNPs. PCA of mtDNA SNPs from persons belonging to A) N macrohaplogroup, B) M macrohaplogroup and C) L macrohaplogroup. The affiliation to haplogroup is shown with color coding. (TIF)

Number and proportion of samples that could not be haplotyped at different steps of the haplotyping and sub-haplotyping. In brackets are given the tables that are referred to in the manuscript. (DOCX)

M-J Networks of mtDNA haplogroups. M-J Network of haplogroups belonging to A) N-macrohaplogroup, B) M macrohaplogroup and C) L macrohaplogroup. (TIF)

Cumulative number of children born of non-Danish citizens as a function of geographical origin. (TIF)

Proportion of different Hg-U subhaplogroups in 1981–1986 and from 2000–2005. U*: All U hgs not belonging to any of the specified U sub-hgs. (DOCX)

Relative proportions of macro-hgs L, M and U in metropolitan and rural areas in 1981–1986 and 2000–2005. (DOCX)

PCAs of A) hg L, B) hg M and C) hg U in 1981–1986 and 2000–2005, PC1: First principal component. PC2: Second principal component. (TIF)

The call-rate of SNPs as a function of the year of deposition of the DBS. (TIF)

Haplogroup and sub-haplogroup defining SNPs and call frequency. (DOCX)

Introduction Approximately 12% of individuals with bipolar disorder (BD) treated with an antidepressant experience antidepressant-induced mania (AIM). Numerous clinical risk factors have been identified but the only genetic risk factor found is the “S” allele or “SS” genotype of HTTLPR, a polymorphism in the promoter region of SLC6A4. We sought to...

Objectives A recent genome‐wide association study (GWAS) in obsessive–compulsive disorder (OCD) reported a significant marker in the dispatched homolog 1 (Drosophila) gene (DISP1 gene) associated with serotonin reuptake inhibitor (SRI) antidepressant response (Qin et al., 2015). DISP1 has never been examined before in terms of association with SRI...

While accounting for only 2% of the body’s weight, the brain utilizes up to 20% of the body’s total energy. Not surprisingly, metabolic dysfunction and energy supply-and-demand mismatch have been implicated in a variety of neurological and psychiatric disorders. Mitochondria are responsible for providing the brain with most of its energetic demands...

Background Schizophrenia (SCZ) is a severe, devastating disorder with a life-time prevalence of 1% irrespective of gender or ethnic group, treated primarily with antipsychotic (AP) medications. Despite clinical efficacy of APs, they are associated with severe side effects including antipsychotic-induced weight gain (AIWG). Methods We investigated...

Background The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility...

Oxidative phosphorylation within mitochondria is the main source of aerobic energy for neuronal functioning, and the key genes are located in mitochondrial DNA. Deficits in oxidative phosphorylation functioning have been reported for schizophrenia, but efforts in the identification of genetic markers within the mitochondrial DNA that predispose to...

Imputation accuracy. The axis Y shows concordance percentages between genotyped and imputed data sets for each of SNP present in the Illumina HumanExome arrays (coding region). (TIF)

Information regarding the genotypes for common SNPs present in the Illumina HumanExome arrays. (XLS)

mtDNA genetic grouping using genotyped data only. Colors correspond to the traditional mtDNA haplogroups according to HaploGrep2. The three clear groups defined by first and second dimensions are highlighted. (TIFF)

Comparison of imputed SNPs frequencies between our study and Saxena et al[25]. (TIF)

List of haplotypes (genotyped/imputed SNPs) found in this study. (XLS)

Haplogroups identified in this study using imputed mtDNA data. (XLSX)

Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes...

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences in haplogroup affiliation and nucl...

Background Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder that has strong genetic risk, but the precise factors remain to be identified. Mitochondria play crucial roles in neurons, such as Ca2+ regulation, redox signaling, development, synaptic plasticity, and apoptosis. The importance of mitochondria in neurons is eviden...

Background Despite its clinical utility, the antipsychotic clozapine (CLZ) has not yet had a promising pharmacogenetic test developed for prediction of response. In the past 20 years, multiple genetic variants (e.g. dopamine, serotonin) have been suggested to be associated with CLZ response. Arranz et al (2000) proposed a model to predict response,...

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the...

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia, and has been interpreted as strong genetic evidence supporting th...

Objectives: Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms...

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individua...

Significance The EPIGEN Brazil Project is the largest Latin-American initiative to study the genomic diversity of admixed populations and its effect on phenotypes. We studied 6,487 Brazilians from three population-based cohorts with different geographic and demographic backgrounds. We identified ancestry components of these populations at a previou...

Objectives: Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associ...

TSPO is a neuroinflammatory biomarker and emerging therapeutic target in psychiatric disorders. We evaluated whether TSPO polymorphisms contribute to interindividual variability in schizophrenia, antipsychotic efficacy and antipsychotic-induced weight gain. We analyzed TSPO polymorphisms in 670 schizophrenia cases and 775 healthy controls. Gene-gen...

Schizophrenia (SCZ) is a severe psychiatric illness with a lifetime prevalence of 0.4 %. A disturbance of energy metabolism has been suggested as part of the etiopathogenesis of the disorder. Several lines of evidence have proposed a connection between etiopathogenesis of SCZ and human brain evolution, which was characterized by an increase in the...

Suicide claims one million lives worldwide annually, making it a serious public health concern. The risk for suicidal behaviour can be partly explained by genetic factors, as suggested by twin and family studies (reviewed in (Zai et al. 2012)). Recently, genome-wide association studies (GWASs) of suicide attempt on large samples of bipolar disorder...

Understanding the peopling of the Americas remains an important and challenging question. Here, we present 14C dates, and morphological, isotopic and genomic sequence data from two human skulls from the state of Minas Gerais, Brazil, part of one of the indigenous groups known as ‘Botocudos’. We find that their genomic ancestry is Polynesian, with n...

Mitochondria are the main source of energy for neurons and play a role in many vital neuronal functions. Mitochondrial dysfunction has been described in schizophrenia, and antipsychotics such as clozapine and olanzapine have been associated with differences in gene expression in mitochondria. We investigated the hypothesis that nuclear-encoded mito...

Background: Suicide is the act of intentionally causing one's own death. The lifetime suicide risk in schizophrenia is 4.9% and 20% to 50% of patients with SCZ will attempt suicide during their life. The other risk factors for suicidal behavior in schizophrenia include prior history of suicide attempts, active psychosis, depression and substance a...

There is a consensus that modern humans arrived in the Americas 15,000-20,000 y ago during the Late Pleistocene, most probably from northeast Asia through Beringia. However, there is still debate about the time of entry and number of migratory waves, including apparent inconsistencies between genetic and morphological data on Paleoamericans. Here w...

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 (MIR137) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis...

A imobilidade pode causar várias complicações que influenciam na recuperação de doenças críticas, incluindo atrofia e fraqueza muscular esquelética. Esse efeito pode ser reduzido com a realização de mobilização precoce no ambiente da UTI (Unidade de Terapia Intensiva), devendo ser considerados fatores neurológicos, circulatórios e respiratórios par...

A large number of studies has investigated the hypothesis that DRD4 48 bp variable number of tandem repeat (VNTR) polymorphism is involved in the etiology of schizophrenia and bipolar disorder. However, the results are inconsistent likely due to genetic and phenotypic heterogeneity. Age at onset (AAO) is considered an important alternate phenotype...

Brazilian Amerindians have experienced a drastic population decrease in the past 500 years. Indeed, many native groups from eastern Brazil have vanished. However, their mitochondrial mtDNA haplotypes, still persist in Brazilians, at least 50 million of whom carry Amerindian mitochondrial lineages. Our objective was to test whether, by analyzing ext...

Supplementary Table 3. Results of database searches for the 13 haplotypes found in Queixadinha on July 2010.

Supplementary Table 5. Sequencing primers used to amplify Botocudo DNA samples in this study, with annealing temperatures.

Supplementary Table 1. Exact test of population differentiation

Supplementary Table 2. Native Americans populations to which Queixadinha and Botocudos sequences were compared.

Supplementary Table 4. Minisequencing results of selected Amerindian haplotypes.

Supplementary Table 6. Restriction fragment length polymorphism primers used to ancient DNA samples in this study, with annealing temperatures.

Approximately four million Africans were taken as slaves to Brazil, where they interbred extensively with Amerindians and Europeans. We have previously shown that while most White Brazilians carry Y chromosomes of European origin, they display high proportions of African and Amerindian mtDNA lineages, because of sex-biased genetic admixture. We stu...