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Introduction to Special Issue: Insight Into Sex Differences in Neuropsychiatric Syndromes From Transcriptomic Analyses

      Sex differences in the incidence of neuropsychiatric disorders have been known for decades. Syndromes as diverse as depression and Alzheimer’s disease are roughly twice as common in females than males, and anorexia nervosa occurs more than an order of magnitude more frequently in females. By contrast, autism spectrum disorder (ASD) is fourfold more common in males, with schizophrenia showing a modest (40%) higher incidence in males. Despite these epidemiological data, it is only relatively recently that insight into the molecular bases of such sex differences is beginning to appear. This progress coincides with the 2016 National Institutes of Health mandate requiring that all National Institutes of Health–funded research consider sex as a biological variable. Prior to this mandate, most clinical investigators focused on male subjects or did not power studies to analyze each sex separately, while most basic laboratories studied male rodents only, reasoning that including females would require several-fold more animals and add too much complexity due to their estrous cycle. Notably, recent efforts suggest that female rodents are in fact not more variable than males (
      • Prendergast B.J.
      • Onishi K.G.
      • Zucker I.
      Female mice liberated for inclusion in neuroscience and biomedical research.
      ,
      • Becker J.B.
      • Prendergast B.J.
      • Liang J.W.
      Female rats are not more variable than male rats: A meta-analysis of neuroscience studies.
      ,
      • Smarr B.
      • Rowland N.E.
      • Zucker I.
      Male and female mice show equal variability in food intake across 4-day spans that encompass estrous cycles.
      ), arguing against excluding females to limit experimental variability. In just 5 short years since the National Institutes of Health mandate, the results have been transformational, as an increasing number of publications have validated and added to a long-standing literature of sex differences in neuroscientific phenomena. The advent of next-generation sequencing approaches (e.g., the quantification of all RNAs expressed in a tissue or given cell type through RNA sequencing) has provided an important additional level of evidence for dramatic sex differences in the biological underpinnings of a range of neuropsychiatric syndromes. This special issue of Biological Psychiatry focuses on these recent transcriptomic datasets and the fundamentally new insights they are providing into the influence of sex on brain function under normal and pathological conditions. Launch of this special issue of Biological Psychiatry coincided with a Neuroscience Forum Workshop sponsored by the National Academies highlighting sex differences in transcriptomic characterization of brain and nervous system disorders (
      National Academies of Sciences, Engineering, and Medicine
      Sex Differences in Brain Disorders: Emerging Transcriptomic Evidence: Proceedings of a Workshop.
      ).
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