Identification and characterization of human GDF15 knockouts.

Area of Science:

• Human genetics
• Metabolic research
• Reproductive biology

Background:

• Growth Differentiation Factor 15 (GDF15) is a secreted protein influencing appetite and stress in preclinical models.
• Human GDF15 function is unclear; pharmacological GDF15 agonism causes nausea, while antagonism targets cachexia.
• Genetic links suggest GDF15's role in hyperemesis gravidarum, but the impact of its complete loss is unknown.

Purpose of the Study:

• To investigate the physiological role and safety of complete Growth Differentiation Factor 15 (GDF15) loss in humans.
• To determine if GDF15 deficiency impacts fertility, pregnancy, development, or overall health.
• To evaluate the implications of GDF15 loss-of-function for therapeutic strategies.

Main Methods:

• Analysis of 75,018 whole-exome/genome-sequenced individuals from the Pakistan Genomic Resource.
• Identification and characterization of homozygous ('knockout') and heterozygous carriers of GDF15 loss-of-function alleles.
• Phenotypic assessment of GDF15 knockout individuals for overt health and metabolic dysfunction.

Main Results:

• Absence of overt phenotypes in human GDF15 loss-of-function carriers, including those with inactivating variants like C211G.
• Identified 8 homozygous and 227 heterozygous GDF15 loss-of-function carriers.
• GDF15 knockouts (aged 31-75) are fertile, have children, and show no consistent metabolic dysfunction or developmental issues.

Conclusions:

• GDF15 is not essential for human fertility, healthy pregnancy, fetal development, or survival into adulthood.
• Complete loss of GDF15 does not result in a discernible adverse phenotype in humans.
• These findings support the safety of developing therapeutics that antagonize GDF15.