Genetic Risk Factors for Amyotrophic Lateral Sclerosis

We performed a genome-wide association study in sporadic ALS (2,323 patients and 9,013 controls) and evaluated all SNPs with P < 1.0 x 10-4 in a second, independent cohort of 2,532 patients and 5,940 controls. Analysis of the genome-wide data revealed genome-wide signifi cance for one SNP, rs12608932 with P = 1.30 x 10-9. This SNP demonstrated robust replication in the second cohort (P = 1.86 x 10-6) and a combined analysis over the two stages yielded a P = 2.53 x 10-14. The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters, such as glutamate, at neuromuscular synapses. Follow-up of additional SNPs demonstrated genome-wide signifi cance for two further SNPs (rs2814707 with P = 7.45 x 10-9 and rs3849942 with P = 1.01 x 10-8) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2 in a linkage region for familial ALS with fronto-temporal dementia found previously in several large pedigrees. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder characterized by progressive wasting and weakness of limb, bulbar, and respiratory muscles. The disease is caused by loss of motor neurons in the spinal cord, brainstem, and motor cortex and can occur at any time in adulthood, with a median age of onset in the mid-fi fties. The incidence of sporadic ALS is 1.5–2.8 per 100,000 population per year with a male predominance (ratio about 1.6:1). About half of patients die within 3 years of symptom onset, because of respiratory failure.1 Currently the only medication to slow the disease is riluzole, which delays progression by 3 months.2 The genetic contribution to sporadic ALS remains largely unknown, despite the considerable estimated heritability ranging from 0.35 to 0.85.3 Candidate gene studies have identifi ed potential risk factors, but replication of these associations has proven to be diffi cult. Similarly, several genome-wide association (GWA) studies have been performed in sporadic ALS, but have not identifi ed irrefutable associations. ITPR2, FGGY and DPP6 have been proposed as candidate susceptibility