Birth order and disease risk across the human phenome
- 1Department of Medicine, University of Chicago, Chicago, IL USA
- 2Department of Psychiatry, Columbia University, New York, NY USA
- 3Department of Human Genetics, Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL USA
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.
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BibTeX
@article{kramer2026birth,
title = {{Birth order and disease risk across the human phenome}},
author = {Benjamin Kramer and Steven A. Kushner and Andrey Rzhetsky},
journal = {Nature Health},
year = {2026},
month = aug,
doi = {10.1038/s44360-026-00177-z},
url = {https://doi.org/10.1038/s44360-026-00177-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Birth order and disease risk across the human phenome
AU - Benjamin Kramer
AU - Steven A. Kushner
AU - Andrey Rzhetsky
PY - 2026
DA - 2026/08/03
JO - Nature Health
DO - 10.1038/s44360-026-00177-z
UR - https://doi.org/10.1038/s44360-026-00177-z
AB - 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.
SN - 3005-0693
ER -