There is currently no gene or SNP described for pathology x but clinical findings suggest it is inherited. If I wanted to investigate the SNP(s) associated with pathology x what would be the best way to go about it? SNP array immediately jumps out at me but I think those typically only scan about 1/10 of genomic SNPs.
Species: Human
Cases: 100
Control: 100
If the pathology x is rare in the population and presumed not to be present in any form in healthy individuals: Exome sequencing and filtering against hundreds of other exomes from healthy controls to remove noise. Enrich for variants with predicted damaging effect, look for shared variants among affected and/or compund heterozygous variants in the same gene(s).
SNP arrays can work for common SNPs but requires follow-up studies anyway. Exome seq can find the causing variant(s) but can be more laborous (the analysis, not the sequencing). You will cover 70-80% or more of the exons in the genome.
One possibility is that the unknown SNP is in high linkage disequilibrium with a known one, in which case the association signal will come with the known SNP. I presume that your question refers to a low-frequency or rare SNP that is not tagged this way. Then you have to do haplotype analysis, assuming that there is at least one haplotype that tags your unknown SNP. Because of the very large number of haplotypes at any given locus, you will be paying a horrendous statistical penalty. This is life. Even if you have the funds to genome or exome sequence all your subjects doesn't solve the problem, actually you end up with a much higher statistical penalty. Good luck
We don't know the heritability or the frequency of the pathology in the population. It's hard to find a good answer. If there are familial sample available, e.g. some of the cases are probands in families cosegregating the disease, that would really help. Again, exome seq. Alternatively deep sequencing of candidate genes and/or genomic regions based on information about the biological processes affected in the disease. About as expensive per sample as for GWAS.
Now I understrand what you mean by "SNP that has not been described".
If there are pedigree data suggestive of monogenic inheritance, a combination of SNP array (for co-segregation and linkage) and exome has a good chance of nailing down the gene. If you don't have serious evidence of monogenic inheritance (dominant, recessive, X-linked or mitochondrial) forget it. You are dealing with a complex trait for which your sample size is totally inadequate.
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