Telephone: 0044 (0) 1223 746057.We conducted a genome-wide meta-analysis of cognitive empathy using the 'Reading the Mind in the Eyes' Test (Eyes Test) in 88,056 Caucasian research participants (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1,497
Caucasian participants (891 females and 606 males) from the Brisbane LongitudinalTwin Study (BLTS). We confirmed a female advantage on the Eyes Test (Cohen's d = 0.21, P < 0.001), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, P meta = 1.57 x 10 -8 ). Common single nucleotide polymorphisms (SNPs) explained 20% of the twin heritability and 5.6% (± 0.76 ; P = 1.72 x 10 -13 ) of the total trait variance in both sexes. Finally, we identified significant genetic correlation between the Eyes Test and measures of empathy (the Empathy Quotient), openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude, and show that the genetic determinants of striatal volumes (caudate nucleus, putamen, and nucleus accumbens) are positively correlated with the genetic determinants of performance on the Eyes Test.Cognitive empathy, defined as the ability to recognize what another person is thinking or feeling, and to predict their behaviour based on their mental states, is vital for interpersonal relationships, which in turn is a key contributor of wellbeing. Cognitive empathy is distinct from affective empathy, defined as the drive to respond to another's mental states with an appropriate emotion1. Difficulties in cognitive empathy have been found in different psychiatric conditions, particularly autism 2 . The dissociation between cognitive and affective empathy (the latter often being intact in autism, for example) suggests these have independent biological mechanisms. Little is known about the genetic correlates of cognitive empathy.Here, we investigated the genetic architecture of this aspect of social cognition using a wellvalidated test, the 'Reading the Mind in the Eyes' Test (Eyes Test). The Eyes Test is a brief online test where participants are shown photographs of the eye regions and have to identify the appropriate emotion or mental state they express 1 . It has been widely used to investigate differences in cognitive empathy in several neuropsychiatric conditions including autism 3 , schizophrenia 4 , bipolar disorder 5 , anorexia nervosa 6 , and major depressive disorder 7 .In collaboration with 23andMe, Inc. we conducted three separate genome-wide association studies (GWASes) of the Eyes Test: a males-only GWAS (n = 43,482), a femalesonly GWAS (n = 44,574), and a non-stratified GWAS (n = 88,056). Study protocol is provided in Figure 1. All participants completed the full version of the Eyes Test online, comprising 36 questions (mean score = 27.47±3.67) (Supplementary Note Section 1). GWAS of the non-stratified and the males-only GWAS did not identify any significant loci. In the females-only analysis, we identified one locus at 3p26.2 that was signi...