rs12148769 (PWRN4): Height and Puberty Timing

Key takeaways

• Identified in a study of 5.4 million people as one of 12,111 variants linked to adult height
• Also among 123 genetic signals for age at menarche in a study of over 182,000 women
• The alternate allele reduces PWRN4 expression in multiple brain regions including the hypothalamus and pituitary
• Both associations meet genome-wide significance, the standard statistical threshold for reliable genetic findings
• Effects on pubertal timing appear to extend to both males and females, not only females

What the research says In a meta-analysis of 5,380,080 individuals, the region containing RNU6-741P and PWRN4 (Prader-Willi Region Non-Protein Coding RNA 4) was among 12,111 single-nucleotide polymorphisms significantly associated with adult height, with the full panel collectively accounting for approximately 40% to 45% of phenotypic variance in height in European-ancestry populations PMID 36224396. This locus also falls among 123 independent signals at 106 genomic regions associated with age at menarche (a female's first menstrual period) identified in up to 182,416 women of European descent, where those 123 signals together explained 2.71% of variance in menarche timing in an independent replication sample of 8,689 women PMID 25231870. Ninety of the 106 menarche loci, including this one, showed consistent directional associations with physical development stage in both boys and girls combined, suggesting the locus broadly regulates pubertal timing across sexes PMID 25231870.

Reported associations

• Adult height: Identified among 12,111 variants significantly associated with height in a meta-analysis of up to 5,380,080 individuals across 281 studies; the full set accounts for approximately 40% (up to 45% when extended to all HapMap 3 reference variants) of phenotypic variance in height among European-ancestry populations PMID 36224396
• Age at menarche: Falls within one of 106 genomic regions harboring 123 independent genome-wide-significant signals for age at menarche in a study of up to 182,416 women across 57 studies; the 123 signals together explained 2.71% of variance in menarche timing in a replication sample of 8,689 women PMID 25231870
• Pubertal timing in both sexes: Menarche-associated loci showed consistent directional effects on Tanner stage (a standard scale of physical maturation) in both girls and boys, with 72 of 106 loci showing consistent effects in boys alone; this pattern suggests a broadly sex-independent role in regulating puberty timing PMID 25231870

Evidence quality The height association derives from one of the largest genetic studies ever conducted, encompassing 281 studies and up to 5,380,080 participants spanning five major ancestry groups, with all reported associations required to meet a genome-wide significance threshold (P < 5 x 10^-8) PMID 36224396. The menarche association comes from 57 studies totaling up to 182,416 women of European descent, with directional concordance confirmed in an independent replication sample of 8,689 women; 104 of 123 signals showed directionally consistent effects in replication, and this locus met genome-wide significance PMID 25231870. No effect size specific to rs12148769 as an individual variant is reported in either study, as both present aggregate results at the level of genomic regions rather than single SNPs, which limits interpretation of this variant's specific magnitude of effect. Prediction accuracy for height drops substantially from approximately 40-45% of variance explained in European-ancestry populations to approximately 10-24% in other ancestries, and comparable limitations apply to generalizing the menarche findings across diverse populations PMID 36224396.

Tissue-specific expression effects

• PWRN4: The alternate allele is associated with reduced expression across seven tissues, including frontal cortex (Brodmann area 9), general cortex, anterior cingulate cortex (Brodmann area 24), hypothalamus, putamen (basal ganglia), caudate nucleus (basal ganglia), and pituitary gland; all observed effects are in the direction of decreased expression, with no tissue showing increased expression GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.