Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

ALS genetic epidemiology ‘How simplex is the genetic epidemiology of ALS?’

“…Recent insights show that the genetics of all ALS (both sporadic and familial) is characterised by a disproportionate contribution of rare genetic variation, as opposed to common complex diseases such as schizophrenia,7 and population-based incidence figures appear to fit well with a so-called discrete multistep process 8. Indeed, rare genetic variation is much more geographically stratified compared with common genetic variation, which is in agreement with the findings in ALS by Zou et al .…”

Comprehensive analysis of the mutation spectrum in 301 German ALS families

“…Thus, besides cosegregation data, we put emphasis on the low frequency of specific variants for our classification, based on the observation that rare and unique alleles contribute most to the heritability of ALS,61 and known monogenic causes of familial ALS represent mostly rare or even private mutations. One exception was principally made for loss-of-function variants in NEK1 with an MAF above 1:10 000, as NEK1 variants have a greatly reduced penetrance,62 although loss-of-function variants in NEK1 were lacking in our German fALS cohort.…”

10 Years of GWAS Discovery: Biology, Function, and Translation

“…49 In the near future, when additive genetic variance will be estimated from WGS data in large samples, the contribution of observed rare and low-frequency variants will be estimated explicitly. Estimates from data available to date provide the first evidence for different genetic architectures between diseases, 50 for example, there is more signal from rare variants for amyotrophic lateral sclerosis (motor neuron disease [MIM: 105400]) than for schizophrenia 51 and more predicted loci for schizophrenia than for immune disorders 52 and hypertension. 53 Theoretical and empirical observations suggest a place for non-additive genetic variation, and there have been many largely unsuccessful attempts to detect epistasis with GWAS data.…”