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This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

Many of the characteristics of psychiatric disorders, including their early age of onset, moderate to high prevalence (i.e., 1% for schizophrenia, >15% for major depression), reduced fecundity, and high heritability have led many to speculate on how risk alleles have persisted throughout evolutionary history. While several potential mechanisms for maintaining high allele frequency of risk variants have been hypothesized (e.g., weak positive selection, balancing selection), few have been empirically tested. Given the recent analytic advancements in detecting polygenic adaptation, we systematically evaluated evidence for selection across a total of twenty-five complex traits including ten neuropsychiatric disorders, three personality traits, total intracranial volume, seven subcortical brain structure volume traits, and four complex traits with no known neuropsychiatric associations. We tested each set of trait-associated variants for evidence of classical hard sweeps (i.e., extreme integrated haplotype scores, iHS), partial sweeps (i.e., extreme population differentiation, Fst), rapid evolution since divergence from Neanderthal (i.e., Neanderthal depletion score, NDS), ancient polygenic selection (i.e., Qx scores), and very recent polygenic selection within the past 2,000 years (i.e., trait singleton density scores, tSDS). Variants associated with schizophrenia (Qx = 208.36, p

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Mutations in the PINK1 gene result in an autosomal recessive form of early-onset PD. PINK1 plays a vital role in mitochondrial quality control via the removal of dysfunctional mitochondria. The aim of the present study was to create a cellular model of PD using siRNA-mediated knock down of PINK1 in SH-SY5Y neuroblastoma cells The possible protective effects of curcumin, known for its many beneficial properties including antioxidant and anti-inflammatory effects, was tested on this model in the presence and absence of paraquat, an additional stressor. PINK1 siRNA and control cells were separated into four treatment groups: (i) untreated, (ii) treated with paraquat, (iii) pre-treated with curcumin then treated with paraquat, or (iv) treated with curcumin. Various parameters of cellular and mitochondrial function were then measured. The PINK1 siRNA cells exhibited significantly decreased cell viability, mitochondrial membrane potential (MMP), mitochondrial respiration and ATP production, and increased apoptosis. Paraquat-treated cells exhibited decreased cell viability, increased apoptosis, a more fragmented mitochondrial network and decreased MMP. Curcumin pre-treatment followed by paraquat exposure rescued cell viability and increased MMP and mitochondrial respiration in control cells, and significantly decreased apoptosis and increased MMP and maximal respiration in PINK1 siRNA cells. These results highlight a protective effect of curcumin against mitochondrial dysfunction and apoptosis in PINK1-deficient and paraquat-exposed cells. More studies are warranted to further elucidate the potential neuroprotective properties of curcumin.

The molecular basis of Parkinson's disease (PD) has been extensively studied in numerous population groups over the past decade. However, very little is known of the molecular etiology of PD in the South African population. We aimed to assess the genetic contribution of parkin mutations to PD pathology by determining the frequency of both point mutations and exon rearrangements in all 12 exons of the parkin gene in a group of 229 South African patients diagnosed with PD. This was done by performing high resolution melt (HRM) as well as multiplex ligation-dependent probe amplification (MLPA) analyses. In total, seven patients (3.1%; 7/229) had either compound heterozygous or homozygous mutations in parkin, and seven patients (3.1%) had heterozygous sequence variants. Two of the patients with parkin mutations are of Black African ancestry. Reverse-transcription PCR on lymphocytes obtained from two patients verified the presence of parkin mutations on both alleles. In conclusion, the present study reveals that mutations in the parkin gene are not a major contributor to PD in the South African population. Further investigations of the molecular etiology of PD in the unique South African population, particularly the Black African and mixed ancestry sub-populations, are warranted.