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<p>Birth-order effects on disease risk have been studied for individual conditions but have not been systematically assessed at phenome-wide scale in large sibling claims cohorts. We apply two complementary designs, a between-family matched cohort (1.6 million pairs) as a high-powered phenome-wide scan, and a within-family sibling comparison (5.1 million families) as an internally controlled sibling contrast, to 569 diseases in Merative MarketScan claims data. Of 418 diseases with adequate case counts, 150 show Bonferroni-significant associations. First-borns carry excess risk for neurodevelopmental conditions (other/unspecified pervasive-developmental-disorder (PDD) code group odds ratio (OR) = 0.57, autism OR = 0.74, attention-deficit/hyperactivity disorder OR = 0.93) and immune-allergic diseases (food allergy OR = 0.80, allergic rhinitis OR = 0.91); second-borns for substance abuse (OR = 1.19) and gastrointestinal conditions (gastritis/duodenitis OR = 1.14). Across diseases analyzed in both designs, between-family and within-family estimates were positively correlated (<i>r</i> = 0.66; 74.2% directionally concordant); 84.7% of Bonferroni-significant between-family hits agreed in direction. Results are robust to state fixed effects (<i>r</i> &gt; 0.99), full-sibling restriction and stricter clinical rematching (<i>r</i> = 0.93). These findings provide a comprehensive map of birth-order effects in the human disease phenome.</p>

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Birth order and disease risk across the human phenome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Benjamin Kramer,
  • Steven A. Kushner,
  • Andrey Rzhetsky

摘要

Birth-order effects on disease risk have been studied for individual conditions but have not been systematically assessed at phenome-wide scale in large sibling claims cohorts. We apply two complementary designs, a between-family matched cohort (1.6 million pairs) as a high-powered phenome-wide scan, and a within-family sibling comparison (5.1 million families) as an internally controlled sibling contrast, to 569 diseases in Merative MarketScan claims data. Of 418 diseases with adequate case counts, 150 show Bonferroni-significant associations. First-borns carry excess risk for neurodevelopmental conditions (other/unspecified pervasive-developmental-disorder (PDD) code group odds ratio (OR) = 0.57, autism OR = 0.74, attention-deficit/hyperactivity disorder OR = 0.93) and immune-allergic diseases (food allergy OR = 0.80, allergic rhinitis OR = 0.91); second-borns for substance abuse (OR = 1.19) and gastrointestinal conditions (gastritis/duodenitis OR = 1.14). Across diseases analyzed in both designs, between-family and within-family estimates were positively correlated (r = 0.66; 74.2% directionally concordant); 84.7% of Bonferroni-significant between-family hits agreed in direction. Results are robust to state fixed effects (r > 0.99), full-sibling restriction and stricter clinical rematching (r = 0.93). These findings provide a comprehensive map of birth-order effects in the human disease phenome.