The rs11150601 intron variant of SETD1A is associated with female schizophrenia in the UK Biobank cohort

BackgroundSchizophrenia is a complex psychiatric disorder with an estimated heritability of 80%. SETD1A, a gene encoding a histone methyltransferase critical for transcriptional regulation, has been identified as a significant risk factor for schizophrenia. Loss-of-function mutations in SETD1A confer up to a 35-fold increased risk, implicating its role in neurodevelopment and synaptic plasticity. MethodsUsing data from the UK Biobank cohort (468,998 participants), we investigated the association of SETD1A variants with schizophrenia, obesity, and hypertension. Schizophrenia cases were identified using ICD-10 codes, while obesity and hypertension were assessed using specific data fields. Genome-wide association analysis was performed using PLINK, and statistical analyses utilized SPSS v26. Logistic regression assessed the impact of SETD1A intron variant (rs11150601) alongside age, obesity, and hypertension on schizophrenia risk. ResultsAmong 1,063 individuals diagnosed with schizophrenia, obesity (p < 0.001) and hypertension (p < 0.001) were significantly more prevalent. The rs11150601 GG genotype was associated with an increased risk of schizophrenia in women (OR 1.6, p < 0.001) but not in men. Logistic regression revealed that obesity, hypertension, and age were independent risk factors for schizophrenia in women. SETD1A genotype exerted a significant sex-specific effect, highlighting its potential role in the biological mechanisms underlying schizophrenia. ConclusionOur findings emphasize the role of SETD1A in the genetic architecture of schizophrenia and its comorbidities, particularly in women. The sex-specific effects of SETD1A variants underscore the importance of incorporating biological sex into studies of psychiatric genetics. Further research is warranted to elucidate the mechanisms by which SETD1A influences neurodevelopment and identify therapeutic strategies targeting its epigenetic functions. Graphical abstractThe rs11150601 intron variant of SETD1A is associated with female schizophrenia but not male schizophrenia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/24318271v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@aa2229org.highwire.dtl.DTLVardef@1a8bc58org.highwire.dtl.DTLVardef@e54cd3org.highwire.dtl.DTLVardef@16c184_HPS_FORMAT_FIGEXP M_FIG C_FIG