Height-reducing variants and selection for short stature in Sardinia

Area of Science:

• Human Genetics
• Population Genetics
• Evolutionary Biology

Background:

• Sardinia's unique genetic landscape offers opportunities to study genetic influences on human traits.
• Understanding genetic factors affecting stature is crucial for human health and evolutionary studies.

Purpose of the Study:

• To identify genetic variants influencing stature in the Sardinian population.
• To investigate the role of rare and founder variants in determining height.
• To explore potential evolutionary selection pressures on stature in Sardinia.

Main Methods:

• Sequencing-based whole-genome association analyses were performed on 6,307 Sardinian individuals.
• Identification and characterization of variants with significant effects on stature.
• Analysis of allele frequencies and inheritance patterns of identified variants.

Main Results:

• Two variants with substantial effects on stature were identified.
• A GHR gene variant (stop codon) associated with Laron syndrome reduces height by 4.2 cm in heterozygotes.
• A KCNQ1 gene variant reduces height by 1.83 cm when maternally inherited.
• Higher frequencies of height-decreasing alleles in Sardinians suggest selection.

Conclusions:

• Rare variants in GHR and KCNQ1 genes play a significant role in stature variation in Sardinia.
• Evidence supports selection for shorter stature in the Sardinian population, potentially an 'island effect'.