rs11634397 (ZFAND6): Type 2 Diabetes Risk
Key takeaways
- rs11634397 near ZFAND6 was one of 12 new type 2 diabetes risk signals in a GWAS combining over 42,000 cases and 98,000 controls of European ancestry
- Effect sizes were modest: allele-specific odds ratios for T2D loci in this study ranged from 1.06 to 1.14
- The alternate allele increases ZFAND6 and FAH expression in the cerebellum, a brain region not typically linked to metabolic disease
- The variant reduces ZFAND6 expression in pituitary tissue and increases CTXND1 expression in heart left ventricle tissue
Key takeaways
- rs11634397 near ZFAND6 was one of 12 new type 2 diabetes susceptibility signals identified in a GWAS meta-analysis combining up to 42,542 cases and 98,912 controls of European ancestry
- Effect sizes were modest: allele-specific odds ratios for T2D loci identified in the study ranged from 1.06 to 1.14
- The alternate allele of this variant increases ZFAND6 and FAH expression in cerebellar brain regions, according to GTEx eQTL data
- The variant also reduces ZFAND6 expression in pituitary tissue and increases CTXND1 expression in heart left ventricle tissue
What the research says A two-stage genome-wide association meta-analysis identified rs11634397, near ZFAND6 (Zinc Finger AN1-type Domain 6), as one of 12 new type 2 diabetes (T2D) susceptibility signals, combining 8,130 cases and 38,987 controls at discovery with replication in up to 34,412 additional cases and 59,925 controls of European descent. In the joint analysis of up to 42,542 cases and 98,912 controls, newly identified loci exceeded genome-wide significance thresholds (P ranging from 2.8x10^-8 to 1.4x10^-22) with allele-specific odds ratios between 1.06 and 1.14. GTEx eQTL data additionally shows that the alternate allele increases FAH (Fumarylacetoacetase) and ZFAND6 expression in cerebellar brain tissue, increases FAH and CTXND1 in heart tissue, and reduces ZFAND6 in pituitary tissue GTEx Portal.
Reported associations
- Type 2 diabetes: rs11634397 near ZFAND6 was identified as one of 12 new genome-wide significant T2D susceptibility signals in a large European-ancestry meta-analysis (up to 42,542 cases and 98,912 controls; combined P < 5x10^-8; allele-specific ORs for the newly identified loci ranged from 1.06 to 1.14)
Evidence quality The T2D association for this locus was identified in a single large two-stage European-ancestry meta-analysis (up to 42,542 cases and 98,912 controls), with genome-wide significance thresholds met across all newly identified loci (P < 5x10^-8). The study reported a genomic inflation factor of 1.07 across discovery cohorts, a value close to 1.0 that the authors interpreted as indicating minimal population stratification bias. A variant-specific odds ratio for rs11634397 individually is not included in the available text; the OR range of 1.06 to 1.14 applies collectively to all newly identified loci in the study. No replication in non-European populations and no conflicting T2D associations are reported in the available data; all evidence originates from a single publication.
Tissue-specific expression effects
- FAH: The alternate allele is associated with increased FAH expression in cerebellar hemisphere and cerebellum brain tissue (the largest observed effects among tested tissues), as well as modestly increased expression in heart atrial appendage and left ventricle GTEx Portal
- ZFAND6: The alternate allele is associated with increased ZFAND6 expression in cerebellar hemisphere and cerebellum, but reduced expression in pituitary tissue GTEx Portal
- CTXND1: The alternate allele is associated with increased CTXND1 expression in heart left ventricle tissue GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is the ZFAND6 gene?
ZFAND6, or Zinc Finger AN1-type Domain 6, is the gene nearest to rs11634397. GTEx data shows the alternate allele of rs11634397 increases ZFAND6 expression in cerebellar brain tissue and reduces it in the pituitary gland.
Is rs11634397 linked to type 2 diabetes?
Yes. rs11634397 was identified as one of 12 genome-wide significant type 2 diabetes susceptibility signals in a large GWAS combining up to 42,542 cases and 98,912 controls of European ancestry.
What is the effect size of rs11634397 on type 2 diabetes risk?
The study that identified rs11634397 reported allele-specific odds ratios between 1.06 and 1.14 across the class of T2D loci it discovered. A variant-specific odds ratio for rs11634397 alone was not included in the available text.
Why does a type 2 diabetes variant affect brain gene expression?
GTEx data shows rs11634397 influences ZFAND6 and FAH expression in the cerebellum. The available studies do not explain the functional connection between this brain expression effect and the type 2 diabetes association.
What is FAH and why is it associated with rs11634397?
FAH, or Fumarylacetoacetase, is a gene involved in amino acid metabolism. GTEx data shows the alternate allele of rs11634397 increases FAH expression in cerebellar and heart tissue, though the connection to the T2D association is not established in the available data.