rs10146335 (FBLN5-TRIP11): Height and ATXN3
Key takeaways
- rs10146335, in the FBLN5-TRIP11 region, was identified as significantly associated with adult height in a study of more than 5.4 million people.
- It is one of 12,111 common genetic variants that together account for nearly all height variation explained by common genetic factors.
- The alternate allele at this position consistently increases expression of the ATXN3 gene across at least 8 body tissues, including nerve, esophagus, thyroid, and adipose tissue.
- Height prediction accuracy using this and similar variants reaches about 40% in European-ancestry populations, but only 10 to 20% in other ancestries.
Key takeaways
- rs10146335, in the FBLN5 - TRIP11 gene region, was identified as significantly associated with adult height in a study of more than 5.4 million people.
- It is one of 12,111 common genetic variants that together account for nearly all height variation explained by common genetic factors.
- The alternate allele at this position consistently increases expression of the ATXN3 gene (ataxin-3) across at least 8 body tissues, including tibial nerve, esophagus, thyroid, and subcutaneous adipose.
- Height prediction accuracy using this and similar variants reaches about 40% of total height variation in European-ancestry populations, but only 10 to 20% in other ancestries.
What the research says rs10146335 is one of 12,111 independent common single-nucleotide polymorphisms (SNPs, positions in the genome where individuals differ by one DNA letter) significantly associated with adult human height, identified in a genome-wide association study (GWAS) of 5,380,080 individuals of diverse ancestries; these variants cluster within roughly 7,209 genomic segments covering about 21% of the human genome and collectively account for nearly all common-variant heritability for height. GTEx v11 expression quantitative trait locus (eQTL) data from 953 donors show that the alternate allele at this locus is associated with increased expression of ATXN3 (ataxin-3) across 8 tissues, with the strongest statistical signal in tibial nerve (p=2.1e-59) and the largest per-allele slope in ovary (+0.78 on a log2 scale) GTEx Portal.
Reported associations
- Adult height: One of 12,111 common SNPs significantly associated with adult human height in a GWAS of 5,380,080 individuals from 281 studies; these variants together explain approximately 40% (or 45% using all HapMap 3 panel SNPs) of height phenotypic variance in European-ancestry populations, and roughly 10-20% (14-24%) in other ancestries
- ATXN3 expression - tibial nerve: The alternate allele is associated with increased ATXN3 expression (slope +0.57, p=2.1e-59) GTEx Portal
- ATXN3 expression - esophagus muscularis: Increased expression (slope +0.57, p=1.3e-52) GTEx Portal
- ATXN3 expression - ovary: Increased expression with the largest observed slope across all tested tissues (+0.78, p=1.7e-20) GTEx Portal
- ATXN3 expression - multiple additional tissues: Increased expression also observed in esophagus gastroesophageal junction (+0.55, p=2.2e-38), thyroid (+0.44, p=1.8e-44), subcutaneous adipose (+0.44, p=4.4e-46), transverse colon (+0.41, p=3.6e-38), and tibial artery (+0.41, p=3.9e-47) GTEx Portal
Evidence quality The height association for rs10146335 derives from the largest height GWAS conducted to date, analyzing 5,380,080 participants from 281 studies of diverse ancestries, providing very high statistical power to detect common-variant associations; no variant-specific p-value or individual effect size for this SNP was reported in the provided study text, as findings were summarized at the level of the full 12,111-SNP set. The GTEx eQTL evidence for ATXN3 expression is notably strong, with all 8 tissues showing highly significant signals (p-values ranging from 1.7e-20 in ovary to 2.1e-59 in tibial nerve) and a consistent positive direction of effect, based on 953 GTEx v11 donors at FDR < 0.05. Height prediction accuracy from the identified variants is considerably lower in non-European populations (roughly 10-20% versus 40% in European ancestry); the study authors indicated this is likely explained by differences in linkage disequilibrium (the statistical tendency for nearby genetic variants to be co-inherited) and allele frequencies within associated regions, rather than different effect sizes or causal regions across ancestries. No conflicting findings are present in the provided sources.
Tissue-specific expression effects
- ATXN3: The alternate allele is associated with increased expression across all 8 tested tissues: tibial nerve, esophageal muscularis, esophagus gastroesophageal junction, thyroid, subcutaneous adipose, transverse colon, tibial artery, and ovary; no tissue shows reduced expression GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs10146335?
rs10146335 is a common genetic variant located near the FBLN5 and TRIP11 genes. It was identified in a large genetic study as one of 12,111 common variants significantly associated with adult human height.
Is rs10146335 linked to height?
Yes. A genome-wide association study of more than 5.4 million people from diverse backgrounds identified this variant as one of 12,111 common genetic positions significantly associated with adult height. Together, these variants explain about 40% of height variation in people of European ancestry.
What effect does rs10146335 have on ATXN3 gene expression?
Data from the GTEx project show that the alternate form of rs10146335 is associated with increased activity of the ATXN3 gene in at least 8 body tissues, including tibial nerve, esophagus, thyroid, and subcutaneous fat. These are statistical associations observed in population data, not evidence of direct causation.
Why is genetic height prediction less accurate in non-European populations?
The study identifying these height variants found accuracy drops from about 40% in European-ancestry populations to roughly 10 to 20% in other ancestries. The authors indicated this is likely explained by differences in linkage disequilibrium and allele frequencies within associated regions, rather than different causal variants across populations.
What is an eQTL?
An eQTL (expression quantitative trait locus) is a genetic variant associated with how actively a nearby gene produces RNA. rs10146335 acts as an eQTL for ATXN3, meaning people with the alternate allele tend to show higher ATXN3 gene activity across multiple tissues.