Birth order and disease risk across the human phenome: evidence from 10 million siblings

Birth order has been implicated in the etiology of individual diseases, but has never been systematically assessed at phenome-wide scale with large administrative claims data and complementary epidemiological designs. Here we use two complementary approaches: a between-family matched cohort of 1.6 million pairs and a within-family sibling comparison which includes 5.1 million families and 10.3 million individuals. These were both applied to 569 diseases defined by the ICD9-CM/ICD10-CM codes in the commercial claim data of Merative MarketScan. Of 418 diseases with adequate case counts, 150 show Bonferroni-significant birth-order associations. All odds ratios compare second-borns with first-borns, so OR < 1 indicates first-born excess. First-borns are at an excessive risk for neurodevelopmental conditions (autism OR = 0.74, ADHD OR = 0.93) and immune-allergic diseases consistent with the hygiene hypothesis (food allergy OR = 0.80, allergic rhinitis OR = 0.91), while second-borns are at an excessive risk for substance abuse (OR = 1.19) and gastrointestinal conditions. Between-family and within-family estimates agree in direction for 84.7% of significant diseases (Pearson r = 0.65), and results are robust to state fixed effects (r = 0.997) and full-sibling restriction. Prespecified validation controls were broadly consistent with expectations. These findings provide a comprehensive map of birth-order effects across the human disease phenome.