No abstract

Hypothyroidism is a common disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. About 12% of the population in the USA will develop substantial thyroid deficiency over their lifetime, mostly as a result of iodine deficiency. The hypothyroidism phenotype also includes individuals that suffer from thyroid development abnormalities (congenital hypothyroidism, CH). Using a large population study, we aimed to identify the functional genes associated with an increase or decreased risk for hypothyroidism (ICD-10, E03). To this end, we used the gene-based proteome-wide association study (PWAS) method to detect associations mediated by the effects of variants on the protein function of all coding genes. The UK-Biobank (UKB) reports on 13,687 cases out of 274,824 participants of European ancestry, with a prevalence of 7.5% and 2.0% for females and males, respectively. The results from PWAS for ICD-10 E03 are a ranked list of 77 statistically significant genes (FDR-q-value <0.05) and an extended list of 95 genes with a weaker threshold (FDR-q-value <0.1). Validation was performed using the FinnGen Freeze 7 (Fz7) database across several GWAS with 33.5k to 44.5k cases. We validated 9 highly significant genes across the two independent cohorts. About 12% of the PWAS reported genes are strictly associated with a recessive inheritance model that is mostly overlooked by GWAS. Furthermore, PWAS performed by sex stratification identified 9 genes in males and 63 genes in females. However, resampling and statistical permutation tests confirmed that the genes involved in hypothyroidism are common to both sexes. Many of these genes function in the recognition and response of immune cells, with a strong signature of autoimmunity. Additional genetic association protocols, including PWAS, TWAS (transcriptional WAS), Open Targets (OT, unified GWAS) and coding-GWAS, revealed the complex etiology of hypothyroidism. Each association method highlights a different facet of the disease, including the developmental program of CH, autoimmunity, gene dysregulation, and sex-related gene enrichment. We conclude that genome association methods are complementary while each one reveals different aspects of hypothyroidism. Applying a multiple-protocol approach to complex diseases is expected to improve interpretability and clinical utility.

Hypothyroidism is a common disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. About 12% of the population in the USA will develop substantial thyroid deficiency over their lifetime, mostly as a result of iodine deficiency. The hypothyroidism phenotype also includes individuals that suffer from thyroid development abnormalities (congenital hypothyroidism, CH). Using a large population study, we aimed to identify the functional genes associated with an increase or decreased risk for hypothyroidism (ICD-10, E03). To this end, we used the gene-based proteome-wide association study (PWAS) method to detect associations mediated by the effects of variants on the protein function of all coding genes. The UK-Biobank (UKB) reports on 13,687 cases out of 274,824 participants of European ancestry, with a prevalence of 7.5% and 2.0% for females and males, respectively. The results from PWAS for ICD-10 E03 are a ranked list of 77 statistically significant genes (FDR-q-value <0.05) and an extended list of 95 genes with a weaker threshold (FDR-q-value <0.1). Validation was performed using the FinnGen Freeze 7 (Fz7) database across several GWAS with 33.5k to 44.5k cases. We validated 9 highly significant genes across the two independent cohorts. About 12% of the PWAS reported genes are strictly associated with a recessive inheritance model that is mostly overlooked by GWAS. Furthermore, PWAS performed by sex stratification identified 9 genes in males and 63 genes in females. However, resampling and statistical permutation tests confirmed that the genes involved in hypothyroidism are common to both sexes. Many of these genes function in the recognition and response of immune cells, with a strong signature of autoimmunity. Additional genetic association protocols, including PWAS, TWAS (transcriptional WAS), Open Targets (OT, unified GWAS) and coding-GWAS, revealed the complex etiology of hypothyroidism. Each association method highlights a different facet of the disease, including the developmental program of CH, autoimmunity, gene dysregulation, and sex-related gene enrichment. We conclude that genome association methods are complementary while each one reveals different aspects of hypothyroidism. Applying a multiple-protocol approach to complex diseases is expected to improve interpretability and clinical utility.

BackgroundEssential hypertension is a polygenic disease that affects almost half of the adult population in the USA. It is a major risk factor for renal, cerebrovascular, and cardiovascular diseases. Previous studies used UK-Biobank (UKB) GWAS results for hypertension to create a polygenic risk score (PRS), with the top and bottom 5% of the PRS translating to a 4-fold difference in the estimated risk. The heritability of hypertension is estimated to be high (30–60%), yet the underlying mechanisms and the associated genes are largely unknown.MethodsIn this study, we used a gene-based method, the proteome-wide association study (PWAS), to detect associations mediated by the effects of variants on protein function. PWAS was applied to individuals of European ancestry from the UKB, with 74,090 cases of clinical diagnosis of essential (primary) hypertension (ICD-10, I10) and 200,734 controls. PWAS aggregates the signal from all variants affecting each coding gene and provides scores for dominant, recessive, and hybrid genetic heritability.ResultsPWAS identified 70 statistically significant associated genes (FDR-q-value <0.05) and 127 genes with a weaker threshold (FDR-q-value <0.1). The overlap with GWAS summary statistics (total 1,362 genes) is only partial, with 23 and 62 genes identified exclusively by PWAS from a total of 70 and 127 genes, respectively), among them 18% were assigned recessive inheritance. Furthermore, PWAS analysis, separately performed on females and males from UKB genotyping imputed data, revealed sex-dependent genetics. There are 22 genes unique in females, with only 2 in males. We identified 6 female-specific genes that were not identified by PWAS for the entire group (70 genes). Only one associated gene (SH2B3) is shared between the sexes. Many of the female-significant genes from PWAS are enriched in cellular immunity functions.ConclusionsWe conclude that hypertension displays sex-dependent genetics with an overlooked recessive inheritance, postulating that the underlying mechanism is substantially different for males and females. Studying hypertension by a gene-based association method improves interpretability and clinical utility.