TY - JOUR
T1 - Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa
T2 - A Cross-trait Genome-Wide Analysis
AU - Lu, Zheng-An
AU - Ploner, Alexander
AU - Birgegård, Andreas
AU - Bulik, Cynthia M
AU - Bergen, Sarah E
AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium
AU - Yilmaz, Zeynep
AU - Petersen, Liselotte Vogdrup
AU - Mortensen, Preben Bo
PY - 2024/9
Y1 - 2024/9
N2 - Background and Hypothesis: Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. Study Design: Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci. Study Results: We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy. Conclusions: This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.
AB - Background and Hypothesis: Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. Study Design: Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci. Study Results: We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy. Conclusions: This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.
KW - GWAS
KW - Mendelian randomization
KW - anorexia
KW - architecture
KW - genetic
KW - nervosa
KW - pleiotropy
KW - polygenic overlap
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85202694920&partnerID=8YFLogxK
U2 - 10.1093/schbul/sbae087
DO - 10.1093/schbul/sbae087
M3 - Journal article
C2 - 38848516
SN - 0586-7614
VL - 50
SP - 1255
EP - 1265
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 5
ER -