ABSTRACT This application is the first, large scale, concerted effort to study sex as a biological variable in human neuroscience through a worldwide brain initiative. We created it to respond to the NIH mandate to address major gaps in knowledge on why some brain disorders are more prevalent in women than men, and vice versa. Women and men differ in aging trends and in the prevalence of major depression, anxiety disorders, substance abuse disorders (SUDs), alcoholism, psychosis, post-traumatic stress disorder (PTSD), and neurodegenerative diseases such as Alzheimer's disease. There are significant sex differences in the brain disorders' mean age of onset, treatment response, symptom severity and disease trajectory. Yet science knows alarmingly little about why. To respond to this, we launch a new worldwide brain initiative: “ENIGMA-SD: Understanding Sex Differences in Global Brain Health through ENIGMA”. ENIGMA's Sex Differences Initiative pools data worldwide to address the “crisis of reproducibility” from underpowered studies (Ioannidis 2014). We bring two sources of innovation: (1) the vast, unprecedented power of a global study across 35 countries, yielding exceptional sensitivity to sex differences and (2) a lifespan approach, to chart disease emergence throughout life, to pick up sex-specific `shifts' in the age of onset, severity, and trajectory of brain disease. We will consistently analyze imaging, genomic, and clinical data from hundreds of institutes - to understand (1) sex differences in brain structure and function across life; and (2) how brain abnormalities differ by sex in five major psychiatric illnesses: major depression (MDD), bipolar disorder (BD), schizophrenia (SCZ), PTSD, and SUDs. We will leverage the success of our ENIGMA consortium - a global study of 18 major brain diseases. Our Aims are: Aim 1. Chart Sex Differences in Brain Aging throughout Life. Building on our largest-ever normative study of the brain in 10,144 people (ENIGMA-Lifespan; Dima 2017), we will create sex-specific lifespan “charts” showing how the brain ages, on average, in women and in men. Using MRI, DTI and resting state fMRI on a worldwide scale, we measure cortical/subcortical brain structures, white matter tracts, and age- sensitive metrics of functional brain synchrony. We develop statistical norms based on age and sex; we test interactions between biological sex and brain aging metrics. Aim 2. Determine Sex Differences in the Trajectory of Brain Deficits in MDD, BD, SCZ, PTSD, and Addictions. Building on our global neuroimaging studies of 5 prevalent brain disorders - we will ask: (1) Are the brain deficits the same in women and men with each disease? (2) Are brain differences greater in women at the same level of clinical severity? Aim 3. Sex and Genetic Risk. In a unique collaboration across our 5 global consortia – ENIGMA-MDD, -BD, -SCZ, -PTSD, and -SUDs – we will compute polygenic risk scores for each disease, and ask: What is the effect on the brain of carrying a higher genetic risk for one of these disorders? Does this effect differ by sex? We will do the groundwork to submit an ENIGMA-wide U01 on Sex Differences in Brain Disease, in 2022.

NARRATIVE Many brain disorders, including depression, PTSD, and anxiety are more prevalent in women than men, but others (such as drug addiction) are more common in men. Here we build on our worldwide consortium, ENIGMA, to study sex differences in brain aging, in the trajectories of 5 major psychiatric illnesses: major depression, bipolar illness, schizophrenia, post-traumatic stress disorder (PTSD), and substance use disorders (SUDs). Our project offers the unprecedented power of a global study across 35 countries, to pick up sex-specific shifts in the age of onset, severity, and trajectory of brain disease across the world.