Previous studies have shown that men and women have different genetic architectures across many traits. However, except waist-to-hip ratio (WHR) and waist circumference (WC), it remains unknown whether the genetic effects of a certain trait are weaker or stronger on men/women. With ∼18 000 Taiwan Biobank subjects, we comprehensively investigate sexual heterogeneity in autosomal genetic effects, for traits regarding cardiovascular health, diabetes, kidney, liver, anthropometric profiles, blood, etc. ‘Gene-by-sex interactions’ (G × S) were detected in 18 out of 26 traits, each with an interaction P-value (PINT) less than 0.05/104 = 0.00048, where 104 is the number of tests conducted in this study. The most significant evidence of G × S was found in WHR (PINT = 3.2 ×10−55) and WC (PINT = 2.3×10−41). As a novel G×S investigation for other traits, we here find that the autosomal genetic effects are weaker on women than on men, for low-density lipoprotein cholesterol (LDL-C), uric acid (UA) and diabetes-related traits such as fasting glucose and glycated hemoglobin. For LDL-C and UA, the evidence of G×S is especially notable in subjects aged less than 50 years, where estrogen can play a role in attenuating the autosomal genetic effects of these two traits. Men and women have systematically distinct environmental contexts caused by hormonal milieu and their specific society roles, which may trigger diverse gene expressions despite the same DNA materials. As many environmental exposures are difficult to collect and quantify, sex can serve as a good surrogate for these factors.