||Slight (1.5x) increase in ALS risk
||Small increase in ALS risk; better lithium response in ALS patients
||Amyotrophic lateral sclerosis
||Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
rs12608932 is a SNP located in an intron of the UNC13A gene which encodes UNC13A, a protein involved with regulation of neurotransmitters like glutamate at central and neuromuscular synpases.
Genome-wide association studies (GWAS) have repeatedly detected a significant but modest association between rs12608932(C) and risk for amyotrophic lateral sclerosis (ALS), with an odds ratio <1.30, but the SNP appears to convey a larger effect on survival in those who actually have ALS. Mean survival in rs12608932(C;C) ALS patients is 6 to 12 months shorter compared those carrying one or two (A) alleles. Approximately 16% of ALS patients are rs12608932(C;C), and a meta-analysis shows that, in contrast to C9orf72-associated ALS patients, treatment with lithium carbonate improved the 12-month survival from 40.1% (CI: 23.2–69.1) to 69.7% (CI: 50.4–96.3).[?dopt=Abstract PMID 28978660 ]
rs12608932(C, reference allele: A) was identified as a risk allele associated with sporadic amyotrophic lateral sclerosis (sALS) or Lou Gehrig’s disease in a two-stage association study with individuals of European ancestry. An initial genome-wide study (2,323 case and 9,013 control subjects) identified SNPs that exhibited P-values less than 1.0x10-4, including rs12608932 (P =1.30x10-9, OR=1.25). These SNPs were further evaluated in a second, independent cohort of individuals (2,532 affected individuals and 5,940 controls). This SNP exhibited significant association in the replication round (P=1.86x10-6, OR=1.20 replication round) with an overall combined P=2.50x10-14. [PMID 19734901]
Two replication studies examining the association of including rs12608932 did not identify any significant association with sALS. The first of these studies was performed with patients from France (285 cases and 285 controls) were genotyped for rs12608932 exhibited P=0.85. [PMID 20385924] The second examined two separate populations of Japanese (1179 cases/1645 controls) and Chinese (684 cases/830 controls) ancestry and found no significant association of rs12608932 with sALS (P=0.67 OR=1.02 for Japanese and P=0.73 OR=1.02 for Chinese). [PMID 21295378] Additionally, the allele frequencies differ between the Eastern Asian population (MAF in Japanese controls: 0.741, cases: 0.746; in Chinese controls: 0.675, cases: 0.681) and the European ancestry population in the initial GWA study that identified rs12608932 as associated with sALS. The minor allele frequency in this study was 0.395 in patients and 0.342 in controls in the first GWAS stage and 0.369 in patients and 0.337 in controls in the second-stage of the study. [PMID 19734901] In both the French and East Asian replication studies, the sample sizes may have been too small to exclude rs12608932(C) as a risk allele for sALS. For example, the power of the Chinese population study was only 63%.
A more recent smaller-scale replication study did identify an association of rs12608932 with sALS in patients of Dutch ancestry (P=0.001). Additionally, the authors collected data on the survivability of patients with sALS and control individuals (of Dutch, Swedish, and Belgian descent) from the previous GWAS which initially associated rs12608932 with ALS [PMID 19734901]. This study showed a weak association with survivability and rs12608932 (P<0.001) when fit to a recessive model. Patients homozygous for the minor allele of rs12608932 (CC) exhibited shorter survival after ALS onset than patients AC or AA by 5 and 10 months in the Dutch population and GWAS cohort, respectively. [PMID 22118904]
[PMID 22118904] UNC13A is a modifier of survival in amyotrophic lateral sclerosis
[PMID 22509407] Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS
[PMID 22921269] UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study.