ENIGMA-SD: Understanding Sex Differences in Global Mental Health through ENIGMA - 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.
