Birth order and disease risk across the human phenome, 2026, Benjamin Kramer et al

[Mij]

Abstract

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.
STUDY

 

[Amw66]

Abstract

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.
STUDY

Interesting - but perhaps only part of the picture.
Perhaps birth order should also take into account stillbirths and miscarriages given the physiological changes involved.